
@article {77379,
	title = {The hypertrophic cardiomyopathy mutations R403Q and R663H increase the number of myosin heads available to interact with actin.},
	journal = {Sci Adv},
	volume = {6},
	year = {2020},
	month = {2020 04},
	pages = {eaax0069},
	abstract = {<p>Hypertrophic cardiomyopathy (HCM) mutations in β-cardiac myosin and myosin binding protein-C (MyBP-C) lead to hypercontractility of the heart, an early hallmark of HCM. We show that hypercontractility caused by the HCM-causing mutation R663H cannot be explained by changes in fundamental myosin contractile parameters, much like the HCM-causing mutation R403Q. Using enzymatic assays with purified human β-cardiac myosin, we provide evidence that both mutations cause hypercontractility by increasing the number of functionally accessible myosin heads. We also demonstrate that the myosin mutation R403Q, but not R663H, ablates the binding of myosin with the C0-C7 fragment of MyBP-C. Furthermore, addition of C0-C7 decreases the wild-type myosin basal ATPase single turnover rate, while the mutants do not show a similar reduction. These data suggest that a primary mechanism of action for these mutations is to increase the number of myosin heads functionally available for interaction with actin, which could contribute to hypercontractility.</p>
},
	issn = {2375-2548},
	doi = {10.1126/sciadv.aax0069},
	author = {Sarkar, Saswata S and Trivedi, Darshan V and Morck, Makenna M and Adhikari, Arjun S and Pasha, Shaik N and Ruppel, Kathleen M and Spudich, James A}
}
@article {74443,
	title = {The Myosin Family of Mechanoenzymes: From Mechanisms to Therapeutic Approaches.},
	journal = {Annu Rev Biochem},
	year = {2020},
	month = {2020 Mar 13},
	abstract = {<p>Myosins are among the most fascinating enzymes in biology. As extremely allosteric chemomechanical molecular machines, myosins are involved in myriad pivotal cellular functions and are frequently sites of mutations leading to disease phenotypes. Human β-cardiac myosin has proved to be an excellent target for small-molecule therapeutics for heart muscle diseases, and, as we describe here, other myosin family members are likely to be potentially unique targets for treating other diseases as well. The first part of this review focuses on how myosins convert the chemical energy of ATP hydrolysis into mechanical movement, followed by a description of existing therapeutic approaches to target human β-cardiac myosin. The next section focuses on the possibility of targeting nonmuscle members of the human myosin family for several diseases. We end the review by describing the roles of myosin in parasites and the therapeutic potential of targeting them to block parasitic invasion of their hosts. Expected final online publication date for the , Volume 89 is June 22, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.</p>
},
	issn = {1545-4509},
	doi = {10.1146/annurev-biochem-011520-105234},
	author = {Trivedi, Darshan V and Nag, Suman and Spudich, Annamma and Ruppel, Kathleen M and Spudich, James A}
}
