2016
DOI: 10.1073/pnas.1609342113
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Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

Abstract: 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 selec… Show more

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Cited by 37 publications
(48 citation statements)
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“…This finding is in agreement with the emerging model that CLD rotation is stabilised by the closure of Switch 2 upon ATP binding rather than being induced by it, so that it can occur at least partially before the changes in the nucleotide binding site take place [12,43,46]. This would also explain the recent observation that myosin can be trapped by inhibitors in intermediate states of the recovery stroke without closure of Switch 2 [12]. Moreover, a decoupling between Switch 2 and lever arm motions is consistent with the recent observation of a new structural state of Myosin VI where a large conformational change of Switch 2 does not produce a corresponding change in the lever arm position [47].…”
Section: Discussionsupporting
confidence: 91%
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“…This finding is in agreement with the emerging model that CLD rotation is stabilised by the closure of Switch 2 upon ATP binding rather than being induced by it, so that it can occur at least partially before the changes in the nucleotide binding site take place [12,43,46]. This would also explain the recent observation that myosin can be trapped by inhibitors in intermediate states of the recovery stroke without closure of Switch 2 [12]. Moreover, a decoupling between Switch 2 and lever arm motions is consistent with the recent observation of a new structural state of Myosin VI where a large conformational change of Switch 2 does not produce a corresponding change in the lever arm position [47].…”
Section: Discussionsupporting
confidence: 91%
“…The motions observed here, while not representing an actual transition to the pre-powerstroke state and while they might have been enhanced by the absence of the Regulatory Domain, suggest a conformational selection scenario for the recovery stroke, where the type of motions involved in the stroke are already partially sampled by the CLD before the binding of ATP. This finding is in agreement with the emerging model that CLD rotation is stabilised by the closure of Switch 2 upon ATP binding rather than being induced by it, so that it can occur at least partially before the changes in the nucleotide binding site take place [12,43,46]. This would also explain the recent observation that myosin can be trapped by inhibitors in intermediate states of the recovery stroke without closure of Switch 2 [12].…”
Section: Discussionsupporting
confidence: 90%
See 1 more Smart Citation
“…Defective myosins were found to be implicated in severe pathologies in humans such as hypertrophic cardiomyopathy (2) and deafness (3), while others, including myosin VI, were shown to have a role in cancer cell proliferation and metastasis (4). Recent studies highlighted the therapeutic potential of small-molecule inhibitors (5) and activators (6)(7)(8) targeting myosin, demonstrating that a detailed knowledge of the force production mechanism in this motor family would facilitate the rational design of drug candidates.…”
mentioning
confidence: 99%
“…We detected free phosphate in solution as described in [46]. 12.5 M cardiac HMM (25 M heads) was manually mixed with 20 M ATP (Sigma-Aldrich), allowed to incubate for 5.0 seconds and quenched with 0.6 M perchloric acid, and detected with malachite green as described in [47].…”
Section: Hydrolysis Of Atpmentioning
confidence: 99%