8QYU

Beta-cardiac myosin S1 fragment in the pre-powerstroke state complexed to Omecamtiv mecarbil

8QYU の概要

• エントリーDOI: 10.2210/pdb8qyu/pdb
• 分子名称: Myosin-7, MALONIC ACID, Myosin light chain 3, ... (11 entities in total)
• 機能のキーワード: cardiac myosin modulators inherited cardiomyopathies omecamtiv mecarbil, contractile protein
• 由来する生物種: Bos taurus (cattle); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 231996.96

構造登録者

Robert-Paganin, J.,Kikuti, C.,Auguin, D.,Rety, S.,David, A.,Houdusse, A. (登録日: 2023-10-26, 公開日: 2023-12-13)

主引用文献

Auguin, D.,Robert-Paganin, J.,Rety, S.,Kikuti, C.,David, A.,Theumer, G.,Schmidt, A.W.,Knolker, H.J.,Houdusse, A.
Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction.
Biorxiv, 2023

PubMed Abstract: Inherited cardiomyopathies are amongst the most common cardiac diseases worldwide, leading in the late-stage to heart failure and death. The most promising treatments against these diseases are small-molecules directly modulating the force produced by β-cardiac myosin, the molecular motor driving heart contraction. Two of these molecules that produce antagonistic effects on cardiac contractility have completed clinical phase 3 trials: the activator and the inhibitor . In this work, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All atoms molecular dynamics simulations reveal how these molecules can have antagonistic impact on the allostery of the motor by comparing β-cardiac myosin in the apo form or bound to or . Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.

PubMed: 38014327
DOI: 10.1101/2023.11.15.567213

実験手法

X-RAY DIFFRACTION (1.96 Å)