Structural basis for drug-induced allosteric changes to human β-cardiac myosin motor activity.

Donald A Winkelmann,Ann M Stock,Eva Forgacs,Matthew T Miller

doi:10.1038/ncomms8974

Donald A Winkelmann, Ann M Stock + Show 2 more

Open Access

https://doi.org/10.1038/ncomms8974

Copy DOI

Abstract

Omecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin that is in clinical trials for treatment of systolic heart failure. A detailed kinetic analysis of cardiac myosin has shown that the drug accelerates phosphate release by shifting the equilibrium of the hydrolysis step towards products, leading to a faster transition from weak to strong actin-bound states. The structure of the human β-cardiac motor domain (cMD) with OM bound reveals a single OM-binding site nestled in a narrow cleft separating two domains of the human cMD where it interacts with the key residues that couple lever arm movement to the nucleotide state. In addition, OM induces allosteric changes in three strands of the β-sheet that provides the communication link between the actin-binding interface and the nucleotide pocket. The OM-binding interactions and allosteric changes form the structural basis for the kinetic and mechanical tuning of cardiac myosin.

Highlights

Omecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin that is in clinical trials for treatment of systolic heart failure
The alternative, expression and purification of recombinant cardiac muscle myosin, had been technically unfeasible until we showed that the principal obstacle for the expression of vertebrate striated muscle myosin was that motor domain folding follows a regulated pathway that is unique to striated muscle cells[9,10,11,12]
The drug binds to the human b-cardiac myosin motor domain in a narrow cleft between the N-terminal 25-K domain and the lower portion of the 50-K domain

Summary

Introduction

Omecamtiv Mecarbil (OM) is a small molecule allosteric effector of cardiac myosin that is in clinical trials for treatment of systolic heart failure. The subtle changes in the kinetic mechanism lead to an increase in the transition rate of weak to strong bound actin states, resulting in increased number of force-producing crossbridges and, paradoxically, a dramatic reduction in the unloaded shortening velocity measured in vitro[6,8] These fascinating kinetic results led to an intense effort to determine the drug-binding site and define the structural interactions within the human b-cardiac myosin motor domain that alter the motor activity. OM binding induces an allosteric change in the conformation of three strands of a b-sheet that are crucial to communication between the nucleotide pocket and actin-binding interface[13] Together, these interactions form the basis of the kinetic and mechanical effects of the drug. This structural analysis characterizes a highly significant binding cleft for drugs designed to modulate myosin motor activity

Methods

Results

Conclusion