@article {158507, title = {Conserved biochemical activity and function of phosphatidylinositol 5 phosphate 4 kinase regulates growth \& development}, year = {2025}, abstract = {

Co-ordination of function between multiple cells, mediated by hormones or growth factors, is a critical requirement for multi-cellularity. Phosphoinositides, generated by lipid kinase activity, are second messengers that mediate such signalling. Phosphatidylinositol 5 phosphate 4-kinase (PIP4K) is a lipid kinase that phosphorylates phosphatidylinositol 5-phosphate (PI5P) to generate phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2]. A comprehensive bioinformatics analysis of the tree of life, revealed that PIP4K is a metazoan-specific enzyme, but with homologs in choanoflagellates. We find that PIP4K from the sponge\ Amphimedon queenslandica\ (AqPIP4K), regarded as the earliest evolved metazoan, shows biochemical activity highly conserved with human PIP4K. Further, AqPIP4K was able to rescue the reduced cell size, growth and development of a\ Drosophila\ PIP4K mutant. These phenotypes are regulated through activity of the insulin receptor, a member of the receptor tyrosine kinase family, that is unique to metazoans. Overall, our work defines PIP4K as part of a signal transduction motif required to regulate receptor tyrosine kinase signalling for intercellular communication in the earliest forms of metazoans.

}, keywords = {Amphimedon queenslandica, Drosophila melanogaster, Growth and development, Insulin signalling, Lipid kinase}, doi = {https://doi.org/10.1242/jcs.263881}, url = {https://journals.biologists.com/jcs/article-abstract/doi/10.1242/jcs.263881/368299/Conserved-biochemical-activity-and-function-of?redirectedFrom=PDF}, author = {Krishnan, H and Muzaffar, S and Sharma, S and Ramya, V and Ghosh, A and Sowdhamini, R and Padinjat, R} } @article {162675, title = {Exploration of Natural Products for Targeting IDH1/2 Mutations in Acute Myeloid Leukemia Through Ligand-Based Pharmacophore Screening, Docking, ADME-T, and Molecular Dynamic Simulation Approaches.}, journal = {Bioinform Biol Insights}, volume = {19}, year = {2025}, month = {2025}, pages = {11779322251399077}, abstract = {

BACKGROUND: Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are prevalent drivers of acute myeloid leukemia (AML). While targeted therapies exist, resistance can emerge. This study explored the potential of natural products to identify novel dual IDH inhibitors.

METHODS: In silico screening of the COCONUT database was performed using Lipinski{\textquoteright}s Rule of Five. Pharmacophore modeling identified crucial features for IDH binding. Docking simulations with Glide (Schr{\"o}dinger) assessed binding affinity, followed by MM-GBSA calculations for free energy estimation. The most promising candidate underwent ADME/T and toxicity analysis. Finally, molecular dynamics (MD) simulations evaluated the stability of protein-ligand complexes and binding interactions, followed by trajectory analysis using dynamical cross-correlation matrix (DCCM) and principal component analysis (PCA).

RESULTS: Ternstroside D (CNP0166496) emerged as a potential dual inhibitor of IDH1 and IDH2 mutations. Docking and MM-GBSA analyses showed strong affinities with IDH1 (-14.2, -84.45 kcal/mol) and IDH2 (-16.8, -60.73 kcal/mol), exceeding those of reference inhibitors GSK321A (-9.6 kcal/mol) and Enasidenib (-8.9 kcal/mol). Key hydrogen-bond interactions with catalytic residues and stable binding during MD simulations support its dual mechanism. ADME/T predictions indicated drug-like properties and a favorable safety profile, highlighting Ternstroside D as a natural scaffold with superior binding compared with existing IDH inhibitors.

CONCLUSION: This in silico study provides compelling evidence for Ternstroside D (CNP0166496) as a promising dual inhibitor for IDH1 and IDH2 mutations in AML. Furthermore, in vitro and in vivo studies are warranted to validate these findings.

}, issn = {1177-9322}, doi = {10.1177/11779322251399077}, author = {Das, Uddalak and Regati, Dheemanth Reddy and Kumar, Jitendra and Sowdhamini, R} } @article {149951, title = {Genome-wide association study reveals effect of nsSNPs on candidate genes in rice during iron deficiency.}, journal = {Funct Integr Genomics}, volume = {24}, year = {2024}, month = {2024 Oct 25}, pages = {198}, abstract = {

Resource-poor areas with moisture deficit lands following aerobic and direct seeded rice (DSR) methods of cultivation face severe problems of iron deficiency. In this study, Bengal and Assam Aus rice panel was phenotyped at the seedling stage using an iron-deprived hydroponic medium for various shoot and root traits. A novel iron deficiency scoring scale was used to classify the tolerance reaction and could range anywhere between 0 and 9, indicating the most tolerant and susceptible, respectively. The GWAS results identified four putative candidate genes; OsFLA for number of leaves and shoot length, OsBIDK1 for root traits; average diameter, volume, biomass, projected area, and surface area, OsHPL3 for chlorophyll index of the third leaf and AKR2B (XBOS252) was for Fe score, (which was earlier reported in relation to Xa21). The nsSNP (nsSNPs) variations in these gene sequences were used to group the panel and identify superior haplotypes and donors. BR16 was identified as a superior donor, with higher chlorophyll index and shoot length than RA23, also higher values for root traits like root average diameter, root volume, root projected area and root surface area followed by Shete Bhado. The impact of identified nsSNPs on protein structure and stability was investigated. The conserved domains detected in the mutated proteins of the superior haplotypes are very informative, highlighting that natural selection favors abiotic stress tolerant variants in resource poor areas. Thus, justifying our choice of Aus landraces for association mapping of Fe deficiency tolerant genes in rice.

}, keywords = {Chlorophyll, Genome-Wide Association Study, Iron Deficiencies, Oryza, Plant Proteins, Plant Roots, Polymorphism, Single Nucleotide}, issn = {1438-7948}, doi = {10.1007/s10142-024-01478-w}, author = {Panda, Siddharth and Anandan, Annamalai and Shafi, K Mohamed and Naika, Mahantesha B N and Sowdhamini, R and Vanishree, G and Sarkar, Sutapa and Travis, Anthony J and Norton, Gareth J and Price, Adam H} } @article {128074, title = {Computational analysis of the flexibility in the disordered linker region connecting LIM domains in cysteine-glycine-rich protein.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1134509}, abstract = {

One of the key proteins that are present in the Z-disc of cardiac tissues, CSRP3, has been implicated in dilated and hypertrophic cardiomyopathy leading to heart failure. Although multiple cardiomyopathy-related mutations have been reported to reside on the two LIM domains and the disordered regions connecting the domains in this protein, the exact role of the disordered linker region is not clear. The linker harbors a few post-translational modification sites and is expected to be a regulatory site. We have carried out evolutionary studies on 5614 homologs spanning across taxa. We also performed molecular dynamics simulations of full-length CSRP3 to show that the length variations and conformational flexibility of the disordered linker could provide additional levels of functional modulation. Finally, we show that the CSRP3 homologs with widely different lengths of the linker regions could display diversity in their functional specifications. The present study provides a useful perspective to our understanding of the evolution of the disordered region between CSRP3 LIM domains.

}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1134509}, author = {Chauhan, Pankaj Kumar and Sowdhamini, R} } @article {133176, title = {Integrated approaches for the recognition of small molecule inhibitors for Toll-like receptor 4.}, journal = {Comput Struct Biotechnol J}, volume = {21}, year = {2023}, month = {2023}, pages = {3680-3689}, abstract = {

Toll-like receptors (TLRs) are pattern recognition receptors present on the surface of cells playing a crucial role in innate immunity. One of the TLRs, TLR4, recognizes LPS (Lipopolysaccharide) as its ligand leading to the release of anti-inflammatory mediators as well as pro-inflammatory cytokines through signal transduction and domain recruitment. TLR4 homodimerizes at its intracellular TIR (Toll/interleukin-1 receptor) domain that helps in the recruitment of the TRAM/TICAM2 (TIR domain-containing adaptor molecule 2) molecule. TRAM also contains TIR domain which in turn, dimerizes and functions as an adapter protein to further recruit TRIF/TICAM1 (TIR domain-containing adaptor molecule 1) protein for mediating downstream signaling. Apart from LPS, TLR4 also recognizes endogenous ligands like fibrinogen, HMGB1, and hyaluronan in autoimmune conditions and sepsis. We employed computational approaches to target TRAM and recognize small molecule inhibitors from small molecules of natural origin, as contained in the Super Natural II database. Finally, cell reporter assays and NMR studies enabled the identification of promising lead compounds. Hence, this study aims to attenuate the signaling of the TLR4-TRAM-TRIF cascade in these auto-inflammatory conditions.

}, issn = {2001-0370}, doi = {10.1016/j.csbj.2023.07.026}, author = {Verma, Shailya and Reddy, Purushotham and Sowdhamini, R} } @article {126669, title = {Structural modelling and dynamics of full-length of TLR10 sheds light on possible modes of dimerization, ligand binding and mechanism of action.}, journal = {Curr Res Struct Biol}, volume = {5}, year = {2023}, month = {2023}, pages = {100097}, abstract = {

Toll like receptors (TLRs) play a pivotal role in innate and adaptive immunity. There are 10 TLRs in the human genome, of which TLR10 is the least characterized. Genetic polymorphism of TLR10 has been shown to be associated with multiple diseases including tuberculosis and rheumatoid arthritis. TLR10 consists of an extracellular domain (ECD), a single-pass transmembrane (TM) helix and intracellular TIR (Toll/Interleukin-1 receptor) domain. ECD is employed for ligand recognition and the intracellular domain interacts with other TIR domain-containing adapter proteins for signal transduction. Experimental structure of ECD or TM domain is not available for TLR10. In this study, we have modelled multiple forms of TLR10-ECD dimers, such as closed and open forms, starting from available structures of homologues. Subsequently, multiple full-length TLR10 homodimer models were generated by utilizing homology modelling and protein-protein docking. The dynamics of these models in membrane-aqueous environment revealed the global motion of ECD and TIR domain towards membrane bilayer. The TIR domain residues exhibited high root mean square fluctuation compared to ECD. The {\textquoteright}closed form{\textquoteright} model was observed to be energetically more favorable than {\textquoteright}open form{\textquoteright} model. The evaluation of persistent interchain interactions, along with their conservation score, unveiled critical residues for each model. Further, the binding of dsRNA to TLR10 was modelled by defined and blind docking approaches. Differential binding of dsRNA to the protomers of TLR10 was observed upon simulation that could provide clues on ligand disassociation. Dynamic network analysis revealed that the {\textquoteright}open form{\textquoteright} model can be the functional form while {\textquoteright}closed form{\textquoteright} model can be the apo form of TLR10.

}, issn = {2665-928X}, doi = {10.1016/j.crstbi.2023.100097}, author = {Tiwari, Vikas and Sowdhamini, R} } @article {126684, title = {Structure modelling of odorant receptor from and identification of potential repellent molecules.}, journal = {Comput Struct Biotechnol J}, volume = {21}, year = {2023}, month = {2023}, pages = {2204-2214}, abstract = {

Odorant receptors (ORs) are important class of proteins involved in olfactory behaviour of insects. These are GPCR-like heptahelical transmembrane proteins with inverted topology compared to GPCR and require a co-receptor (ORco) for their function. OR function can be modulated through small molecules and negative modulation can be beneficial in case of disease vectors like . OR4 of is implicated in host recognition through human odour. is a vector for viruses that spread diseases like dengue, Zika and Chikungunya. In this study, we have attempted to model the full-length structure of OR4 and the ORco of due to lack of experimental structure. Further, we have screened a library of natural compounds (\>0.3 million) along with known repellent molecules against ORco and OR4. Many natural compounds, including those from plants like (Holy Basil) and (Black pepper) were found to have better binding affinity towards ORco compared to known repellents like DEET providing an alternative to existing repellent molecules. For specific inhibitor of OR4, several natural compounds (including those from plant like Mulberry) were identified. Further, we have utilized multiple docking approaches and conservation analysis to understand the interaction between OR4 and ORco. It was observed that the residues from the seventh transmembrane helix of OR4 and pore forming helix of ORco could play an important role along with known intracellular loop 3 residues in mediating the heteromer formation of OR and ORco.

}, issn = {2001-0370}, doi = {10.1016/j.csbj.2023.03.005}, author = {Tiwari, Vikas and Sowdhamini, R} } @article {123114, title = {{\textquoteleft}Priming{\textquoteright} protects Piper nigrum L. from Phytophthora capsici through reinforcement of phenylpropanoid pathway and possible enhancement of Piperine biosynthesis }, journal = {Front. Plant Sci.}, volume = {13}, year = {2022}, month = {12/2022}, abstract = {

Piper nigrum L. (black pepper), a woody perennial spice crop indigenous to India is positioned at the phylogenetically unique basal lineage of angiosperms. Cultivation of this major spice crop is constrained by rampant fungal and viral infections leading to a lack of disease-free planting material. The major disease that poses severe threat to P. nigrum plantations and nurseries is {\textquoteleft}quick wilt{\textquoteright} caused by the oomycete Phytophthora capsici, which affects the leaf, stem, spike, collar and root. In this paper, we report the consequence of priming in modulating Piper nigrum defense against Phytophthora capsici. Glycol Chitosan (GC) was used to infiltrate detached leaves of mature P. nigrum plants. It was observed that pre-treatment of GC for 24 hours resulted in significant reduction of disease symptoms in infected leaves, as evidenced by the marked decrease in the size of lesions, and also delayed the appearance of symptoms up to 72 hpi. Experiments repeated in P. nigrum seedlings under controlled growth conditions indicate that delayed disease symptoms of GC pre-treated leaves do not spread to healthy uninfiltrated leaves suggesting a priming-associated systemic defense response. An ROS-mediated manifestation of Hypersensitive Response (HR) induced by Chitosan was also evident in pre-treated leaves. A corresponding visual indication of increased lignification was observed, which correlated with an enhanced lignin content of GC-treated leaves. Enhanced callose deposition was also apparent in GC infiltrated leaves, establishing a stimulatory effect of GC in triggering HR through ROS production, enhanced lignification and callose deposition. Key genes of the core phenylpropanoid and isoprenoid pathways along with major defense signalling pathway genes of P. nigrum, including pathogenesis-related genes and hormone signalling genes showed significant transcript enrichment consequential to GC treatment. A significant quantitative enhancement in Piperine content was evident in GC-infiltrated leaves. The systemic nature of priming on disease protection was established through experiments conducted in rooted cuttings monitored for 30 days after disease infection. This is the first report that provides strong molecular evidence endorsing the twofold advantage of defense priming in P. nigrum by improving crop protection with a concomitant enhancement in Piperine biosynthesis.

}, doi = {10.3389/fpls.2022.1072394}, author = {Indu, M and Meera, B and Sivakumar, K and Mahadevan, C and Shafi, K and Nagarathnam, B and Sowdhamini, R and Sakuntala, M} } @article {88161, title = {Chronic exposure of humans to high level natural background radiation leads to robust expression of protective stress response proteins.}, journal = {Sci Rep}, volume = {11}, year = {2021}, month = {2021 Jan 19}, pages = {1777}, abstract = {

Understanding exposures to low doses of ionizing radiation are relevant since most environmental, diagnostic radiology and occupational exposures lie in this region. However, the molecular mechanisms that drive cellular responses at these doses, and the subsequent health outcomes, remain unclear. A local monazite-rich high level natural radiation area (HLNRA) in the state of Kerala on the south-west coast of Indian subcontinent show radiation doses extending from <= 1 to >= 45\ mGy/y and thus, serve as a model resource to understand low dose mechanisms directly on healthy humans. We performed quantitative discovery proteomics based on multiplexed isobaric tags (iTRAQ) coupled with LC-MS/MS on human peripheral blood mononuclear cells from HLNRA individuals. Several proteins involved in diverse biological processes such as DNA repair, RNA processing, chromatin modifications and cytoskeletal organization showed distinct expression in HLNRA individuals, suggestive of both recovery and adaptation to low dose radiation. In protein-protein interaction (PPI) networks, YWHAZ (14-3-3ζ) emerged as the top-most hub protein that may direct phosphorylation driven pro-survival cellular processes against radiation stress. PPI networks also identified an integral role for the cytoskeletal protein ACTB, signaling protein PRKACA; and the molecular chaperone HSPA8. The data will allow better integration of radiation biology and epidemiology for risk assessment [Data are available via ProteomeXchange with identifier PXD022380].

}, issn = {2045-2322}, doi = {10.1038/s41598-020-80405-y}, author = {Nishad, S and Chauhan, Pankaj Kumar and Sowdhamini, R and Ghosh, Anu} } @article {78101, title = {Homology modeling identifies crucial amino-acid residues that confer higher Na+ transport capacity of OcHKT1;5 from Oryza coarctata Roxb.}, journal = {Plant Cell Physiol}, year = {2020}, month = {2020 May 07}, abstract = {

HKT1;5 loci/alleles are important determinants of crop salinity tolerance. HKT1;5s encode plasmalemma-localized Na+-transporters, retrieving xylem Na+ into xylem parenchyma cells, reducing shoot Na+ accumulation. Allelic variation in rice OsHKT1;5 sequence in specific landraces (Nona Bokra OsHKT1;5-NB/Nipponbare OsHKT1;5-Ni) correlates with variation in salt tolerance. Oryza coarctata, a halophytic wild rice, grows in fluctuating salinity at the seawater-estuarine interface in Indian and Bangladeshi coastal regions. The distinct transport characteristics of the shoots and roots expressing O. coarctata OcHKT1;5 transporter, are reported vis-{\`a}-vis OsHKT1;5-Ni. Yeast sodium extrusion-deficient cells expressing\ OcHKT1;5 are sensitive to increasing Na+ (10-100 mM). Electrophysiological measurements in Xenopus oocytes expressing O. coarctata or rice HKT1;5 transporters indicates that OcHKT1;5, like OsHKT1;5-Ni is a Na+-selective transporter, but displays 16-fold lower affinity for Na+ and 3.5-fold higher maximal conductance than OsHKT1;5-Ni. For Na+ concentrations greater than 10 mM, OcHKT1;5 conductance is higher than that of OsHKT1;5-Ni, indicating potential of OcHKT1;5 for increasing domesticated rice salt tolerance. Homology modeling/ simulation suggests that four key amino acid changes in OcHKT1;5 (in loops on the extracellular side; E239K, G207R, G214R, L363V), account for its lower affinity and higher Na+ conductance vis-{\`a}-vis OsHKT1;5-Ni. Of these, E239K in OcHKT1;5, confers lower affinity for Na+ transport, as evidenced by Na+ transport assays of reciprocal site directed mutants for both transporters (OcHKT1;5- K239E, OsHKT1;5-Ni- E270K) in Xenopus oocytes. Both transporters have analogous roles in xylem sap desalinization and differences in Na+ transport affinity/ conductance between the transporters is attributable to differences in xylem sap Na+ concentrations in both species.

}, issn = {1471-9053}, doi = {10.1093/pcp/pcaa061}, author = {Somasundaram, Suji and V{\'e}ry, Anne-Ali{\'e}nor and Vinekar, Rithvik S and Ishikawa, Tetsuya and Kumari, Kumkum and Pulipati, Shalini and Kumaresan, Kavitha and Corratg{\'e}-Faillie, Claire and Sowdhamini, R and Parida, Ajay and Shabala, Lana and Shabala, Sergey and Venkataraman, Gayatri} } @article {86450, title = {Molecular and functional characterization of buffalo nasal epithelial odorant binding proteins and their structural insights by in silico and biochemical approaches}, journal = {J Biomol Struct Dyn}, year = {2020}, month = {12/2020}, pages = {1-24}, abstract = {

The olfactory system is capable of detecting and distinguishing thousands of environmental odorants that play a key role in reproduction, social behaviours including pheromones influenced classical events. Membrane secretary odorant binding proteins (OBPs) are soluble lipocalins, localized in the nasal membrane of mammals. They bind and carry odorants within the nasal epithelium to putative olfactory transmembrane receptors (ORs). OBP has not yet been exploited to develop a suitable technique to detect oestrus which is being reported as a difficult task in buffalo. In the present study, using molecular biology and protein engineering approaches, we have cloned six novel OBP isoforms from buffalo nasal epithelium odorant-binding proteins (bnOBPs). Furthermore, 3 D models were developed and molecular-docking, dynamics experiments were performed by in silico approaches. In particular, we found four residues (Phe104, Phe134, Phe69 and Asn118) in OBP1a, which contributed to favourable interactions towards two sex pheromones, specifically oleic acid and p-cresol. We expressed this protein in Escherichia coli from female buffalo urine and validated through fluorescence quenching studies to show similar strong binding affinities of OBP1a to oleic acid and p-cresol. By using structural data, the binding specificity was also verified by site-directed mutagenesis of the four residues followed by in vitro binding assays. Our results enable us to better understand the functions of different nasal epithelium OBP isoforms in buffaloes. They also lead to improved understanding of the interaction between olfactory proteins and odorants to develop highly selective biosensing devices for non-invasive detection of oestrus in buffaloes. Communicated by Ramaswamy H. Sarma.

}, doi = {10.1080/07391102.2020.1854117}, author = {Manikkaraja, C and Bhavika, M and Singh, R and Nagarathnam, B and George, G and Gulyani, A and Archunan, G and Sowdhamini, R} } @article {81591, title = {Quaternary variations in the structural assembly of N-acetylglucosamine-6-phosphate deacetylase from Pasteurella multocida.}, journal = {Proteins}, year = {2020}, month = {2020 Aug 31}, abstract = {

N-acetylglucosamine 6-phosphate deacetylase (NagA) catalyzes the conversion of N-acetylglucosamine-6-phosphate to glucosamine-6-phosphate in amino sugar catabolism. This conversion is an essential step in the catabolism of sialic acid in several pathogenic bacteria, including Pasteurella multocida, and thus NagA is identified as a potential drug target. Here, we report the unique structural features of NagA from P. multocida (PmNagA) resolved to 1.95 {\r a}. PmNagA displays an altered quaternary architecture with unique interface interactions compared to its close homolog, the Escherichia coli NagA (EcNagA). We confirmed that the altered quaternary structure is not a crystallographic artefact using single particle electron cryo-microscopy. Analysis of the determined crystal structure reveals a set of hot-spot residues involved in novel interactions at the dimer-dimer interface. PmNagA binds to one Zn ion in the active site and demonstrates kinetic parameters comparable to other bacterial homologs. Kinetic studies reveal that at high substrate concentrations (~10-fold the K ), the tetrameric PmNagA displays hysteresis similar to its distant neighbor, the dimeric Staphylococcus aureus NagA (SaNagA). Our findings provide key information on structural and functional properties of NagA in P. multocida that could be utilized to design novel antibacterials. This article is protected by copyright. All rights reserved.

}, issn = {1097-0134}, doi = {10.1002/prot.25996}, author = {Manjunath, Lavanyaa and Coombes, David and Davies, James and Dhurandhar, Mugdha and Tiwari, Vikas R and Dobson, Renwick C J and Sowdhamini, R and Ramaswamy, S and Bose, Sucharita} } @article {59713, title = {EcRBPome: a comprehensive database of all known E. coli RNA-binding proteins.}, journal = {BMC Genomics}, volume = {20}, year = {2019}, month = {2019 May 22}, pages = {403}, abstract = {

The repertoire of RNA-binding proteins (RBPs) in bacteria play a crucial role in their survival, and interactions with the host machinery, but there is little information, record or characterisation in bacterial genomes. As a first step towards this, we have chosen the bacterial model system Escherichia coli, and organised all RBPs in this organism into a comprehensive database named EcRBPome. It contains RBPs recorded from 614 complete E. coli proteomes available in the RefSeq database (as of October 2018). The database provides various features related to the E. coli RBPs, like their domain architectures, PDB structures, GO and EC annotations etc. It provides the assembly, bioproject and biosample details of each strain, as well as cross-strain comparison of occurrences of various RNA-binding domains (RBDs). The percentage of RBPs, the abundance of the various RBDs harboured by each strain have been graphically represented in this database and available alongside other files for user download. To the best of our knowledge, this is the first database of its kind and we hope that it will be of great use to the biological community.

}, issn = {1471-2164}, doi = {10.1186/s12864-019-5755-5}, author = {Ghosh, Pritha and Joshi, Adwait and Guita, Niang and Offmann, Bernard and Sowdhamini, R} } @article {36666, title = {Evaluating Ylehd, a recombinant epoxide hydrolase from Yarrowia lipolytica as a potential biocatalyst for the resolution of benzyl glycidyl ether}, journal = {RSC ADVANCES}, volume = {8}, year = {2018}, month = {2018}, pages = {12918-12926}, doi = {10.1039/c8ra00628h}, author = {Bendigiri, C and Harini, K and Yenkar, S and Zinjarde, S and Sowdhamini, R and RaviKumar, A} } @article {23142, title = {Computational genome-wide survey of odorant receptors from two solitary bees Dufourea novaeangliae (Hymenoptera: Halictidae) and Habropoda laboriosa (Hymenoptera: Apidae).}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 Sep 07}, pages = {10823}, abstract = {

Olfactory/odorant receptors (ORs) probably govern eusocial behaviour in honey bees through detection of cuticular hydrocarbons (CHCs) and queen mandibular gland pheromones (QMP). CHCs are involved in nest-mate recognition whereas QMP acts as sex pheromone for drones and as retinue pheromone for female workers. Further studies on the effect of eusociality on the evolution of ORs are hindered by the non-availability of comprehensive OR sets of solitary species. We report complete OR repertoires from two solitary bees Dufourea novaeangliae (112 ORs) and Habropoda laboriosa (151 ORs). We classify these ORs into 34 phylogenetic clades/subfamilies. Differences in the OR sets of solitary and eusocial bees are observed in individual subfamilies like subfamily 9-exon (putative CHC receptors) and L (contains putative QMP receptor group). A subfamily (H) including putative floral scent receptors is expanded in the generalist honey bees only, but not in the specialists. On the contrary, subfamily J is expanded in all bees irrespective of their degree of social complexity or food preferences. Finally, we show species-lineage specific and OR-subfamily specific differences in the putative cis-regulatory DNA motifs of the ORs from six hymenopteran species. Out of these, [A/G]CGCAAGCG[C/T] is a candidate master transcription factor binding site for multiple olfactory genes.

}, issn = {2045-2322}, doi = {10.1038/s41598-017-11098-z}, author = {Karpe, Snehal D and Dhingra, Surbhi and Brockmann, Axel and Sowdhamini, R} } @article {18676, title = {Editorial-Sequences and topology.}, journal = {Curr Opin Struct Biol}, year = {2017}, month = {2017 Jun 03}, issn = {1879-033X}, doi = {10.1016/j.sbi.2017.05.006}, author = {Sowdhamini, R and Mizuguchi, Kenji} } @article {3554, title = {Genome-wide survey of putative RNA-binding proteins encoded in the human proteome.}, journal = {Mol Biosyst}, volume = {12}, year = {2016}, month = {2016 Jan 26}, pages = {532-40}, abstract = {

RNA-binding proteins (RBPs) are involved in various post-transcriptional gene regulatory processes and are also functionally important members of the ribosome and the spliceosome. However, RBPs and their interactions with RNA are less well-studied in comparison to DNA-binding proteins. We have classified the existing RBP structures, available in complexes with RNA and RNA/DNA hybrids, into different structural families and created Hidden Markov Models (HMMs). These structure-centric family HMMs, along with the sequence-centric family HMMs, were used as a primary database to systematically search the human proteome for the presence of putative RBPs. We have found more than 2600 gene products with RBP signatures in humans, of which around 28\% are likely to bind to RNA but not DNA, whereas 9\% might bind to both RNA and DNA. 11\% of them do not contain an explicit functional annotation yet. Nearly 30\% of the putative RBPs are exclusively nuclear, 15\% have known disease associations and around 30\% are enzymes. Around 40\% of the proteins identified in this study are novel and have not been reported by recent large-scale studies on human RBPs.

}, issn = {1742-2051}, doi = {10.1039/c5mb00638d}, author = {Ghosh, Pritha and Sowdhamini, R} } @article {1023, title = {Molecular modelling of human 5-hydroxytryptamine receptor (5-HT2A) and virtual screening studies towards the identification of agonist and antagonist molecules.}, journal = {J Biomol Struct Dyn}, volume = {34}, year = {2016}, month = {05/2016}, pages = {952-70}, chapter = {952}, abstract = {

The serotonin receptors, also known as 5-hydroxytryptamine (5-HT) receptors, are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels found in the central and peripheral nervous systems. GPCRs have a characteristic feature of activating different signalling pathways upon ligand binding and these ligands display several efficacy levels to differentially activate the receptor. GPCRs are primary drug targets due to their central role in several signal transduction pathways. Drug design for GPCRs is also most challenging due to their inherent promiscuity in ligand recognition, which gives rise to several side effects of existing drugs. Here, we have performed the ligand interaction study using the two prominent states of GPCR, namely the active and inactive state of the 5-HT2A receptor. Active state of 5-HT2A receptor model enhances the understanding of conformational difference which influences the ligand-binding site. A 5-HT2A receptor active state model was constructed by homology modelling using active state β2-adrenergic receptor (β2-AR). In addition, virtual screening and docking studies with both active and inactive state models reveal potential small molecule hits which could be considered as agonist-like and antagonist-like molecules. The results from the all-atom molecular dynamics simulations further confirmed that agonists and antagonists interact in different modes with the receptor.

}, issn = {1538-0254}, doi = {10.1080/07391102.2015.1062802}, author = {Gandhimathi, A and Sowdhamini, R} } @article {3558, title = {PASS2 database for the structure-based sequence alignment of distantly related SCOP domain superfamilies: update to version 5 and added features.}, journal = {Nucleic Acids Res}, volume = {44}, year = {2016}, month = {2016 Jan 4}, pages = {D410-4}, abstract = {

Structure-based sequence alignment is an essential step in assessing and analysing the relationship of distantly related proteins. PASS2 is a database that records such alignments for protein domain superfamilies and has been constantly updated periodically. This update of the PASS2 version, named as PASS2.5, directly corresponds to the SCOPe 2.04 release. All SCOPe structural domains that share less than 40\% sequence identity, as defined by the ASTRAL compendium of protein structures, are included. The current version includes 1977 superfamilies and has been assembled utilizing the structure-based sequence alignment protocol. Such an alignment is obtained initially through MATT, followed by a refinement through the COMPARER program. The JOY program has been used for structural annotations of such alignments. In this update, we have automated the protocol and focused on inclusion of new features such as mapping of GO terms, absolutely conserved residues among the domains in a superfamily and inclusion of PDBs, that are absent in SCOPe 2.04, using the HMM profiles from the alignments of the superfamily members and are provided as a separate list. We have also implemented a more user-friendly manner of data presentation and options for downloading more features. PASS2.5 version is available at http://caps.ncbs.res.in/pass2/.

}, issn = {1362-4962}, doi = {10.1093/nar/gkv1205}, author = {Gandhimathi, Arumugam and Ghosh, Pritha and Hariharaputran, Sridhar and Mathew, Oommen K and Sowdhamini, R} } @article {1029, title = {A tale of two paralogs: human Transformer2 proteins with differential RNA-binding affinities.}, journal = {J Biomol Struct Dyn}, volume = {34}, year = {2016}, month = {2015 Nov 26}, pages = {1979-86}, chapter = {1979}, abstract = {

The Transformer2 (Tra2) proteins in humans are homologues of the Drosophila Tra2 protein. One of the two RNA-binding paralogs, Tra2β, has been very well-studied over the past decade, but not much is known about Tra2α. It was very recently shown that the two proteins demonstrate the phenomenon of paralog compensation. Here, we provide a structural basis for this genetic backup circuit, using molecular modelling and dynamics studies. We show that the two proteins display similar binding specificities, but differential affinities to a short GAA-rich RNA stretch. Starting from the 6-nucleotide RNA in the solution structure, close to 4000 virtual mutations were modelled on RNA and the domain-RNA interactions were studied after energy minimisation to convergence. Separately, another known 13-nucleotide stretch was docked and the domain-RNA interactions were observed through a 100-ns dynamics trajectory. We have also demonstrated the {\textquoteright}compensatory{\textquoteright} mechanism at the level of domains in one of the domain repeat-containing RNA-binding proteins.

}, issn = {1538-0254}, doi = {10.1080/07391102.2015.1100551}, author = {Ghosh, Pritha and Grellscheid, Sushma Nagaraja and Sowdhamini, R} } @article {1040, title = {161 Bridging the islands of protein families in sequence space using artificial sequences.}, journal = {J Biomol Struct Dyn}, volume = {33 Suppl 1}, year = {2015}, month = {2015}, pages = {103-4}, issn = {1538-0254}, doi = {10.1080/07391102.2015.1032798}, author = {Srinivasan, N and Mudgal, R and Kumar, G and Chandra, N R and Sowdhamini, R and Sandhya, S} }