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标题：Highly selective inhibition of myosin motors provides the basis of potential therapeutic application
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作者：Serena Sirigu ; James J. Hartman ; Vicente José Planelles-Herrero 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：47
页码：E7448-E7455
DOI：10.1073/pnas.1609342113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDefects in myosin function are linked to a number of widespread and debilitating diseases, including asthma, chronic obstructive pulmonary disease, and hypertrophic cardiomyopathy. We report here the discovery of an allosteric site that modulates myosin motor function with high specificity that opens the path toward new therapeutic solutions. Identification of specific antimyosin drugs that significantly alter a motors function is an imperative first step toward the development of targeted and effective treatments for such diseases. Highly specific drugs against different members of the superfamily would also provide exquisite tools to investigate in cells their functional role. Additionally, detailed, high-resolution studies of the interaction of drugs with their myosin targets provide insights into the molecular mechanism of motor function. Direct inhibition of smooth muscle myosin (SMM) is a potential means to treat hypercontractile smooth muscle diseases. The selective inhibitor CK-2018571 prevents strong binding to actin and promotes muscle relaxation in vitro and in vivo. The crystal structure of the SMM/drug complex reveals that CK-2018571 binds to a novel allosteric pocket that opens up during the "recovery stroke" transition necessary to reprime the motor. Trapped in an intermediate of this fast transition, SMM is inhibited with high selectivity compared with skeletal muscle myosin (IC50 = 9 nM and 11,300 nM, respectively), although all of the binding site residues are identical in these motors. This structure provides a starting point from which to design highly specific myosin modulators to treat several human diseases. It further illustrates the potential of targeting transition intermediates of molecular machines to develop exquisitely selective pharmacological agents.
关键词：myosin ; actin ; drug design ; molecular motor ; specific allosteric drugs