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Structural and Computational Insights into a Blebbistatin-Bound Myosin•ADP Complex with Characteristics of an ADP-Release Conformation along the Two-Step Myosin Power Stoke

  • The motor protein myosin drives a wide range of cellular and muscular functions by generating directed movement and force, fueled through adenosine triphosphate (ATP) hydrolysis. Release of the hydrolysis product adenosine diphosphate (ADP) is a fundamental and regulatory process during force production. However, details about the molecular mechanism accompanying ADP release are scarce due to the lack of representative structures. Here we solved a novel blebbistatin-bound myosin conformation with critical structural elements in positions between the myosin pre-power stroke and rigor states. ADP in this structure is repositioned towards the surface by the phosphate-sensing P-loop, and stabilized in a partially unbound conformation via a salt-bridge between Arg131 and Glu187. A 5 Å rotation separates the mechanical converter in this conformation from the rigor position. The crystallized myosin structure thus resembles a conformation towards the end of the two-step power stroke, associated with ADP release. Computationally reconstructing ADP release from myosin by means of molecular dynamics simulations further supported the existence of an equivalent conformation along the power stroke that shows the same major characteristics in the myosin motor domain as the resolved blebbistatin-bound myosin-II·ADP crystal structure, and identified a communication hub centered on Arg232 that mediates chemomechanical energy transduction.

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Document Type:Article
Author:Wiebke Ewert, Peter Franz, Georgios Tsiavaliaris, Matthias Preller
Parent Title (English):International Journal of Molecular Sciences
Article Number:7417
Number of pages:24
Place of publication:Basel
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2020/10/08
Copyright:© 2020 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
Funding:This research work was funded by the Deutsche Forschungsgemeinschaft (DFG), grant numbers TS169/5-1 (G.T.) and PR1478/2-1 (M.P.).
Keyword:ADP release; blebbistatin; cytoskeleton; force generation; molecular dynamics simulations; molecular motor; myosin; structural biology
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für Technik, Ressourcenschonung und Energieeffizienz (TREE)
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Fields of research:Institut für Technik, Ressourcenschonung und Energieeffizienz (TREE) / Arbeitsgruppe Computational Chemistry
Entry in this database:2020/10/17
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International