9F6C

Cardiac myosin motor domain in the pre-powerstroke state co-crystallized with the inhibitor aficamten

9F6C の概要

• エントリーDOI: 10.2210/pdb9f6c/pdb
• 分子名称: Myosin-7, SULFATE ION, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: cardiac myosin, modulator, cardiomyopathy, force production, motor protein
• 由来する生物種: Bos taurus (cattle)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 180533.97

構造登録者

Robert-Paganin, J.,Hartman, J.J.,Morgan, B.P.,Malik, F.I.,Houdusse, A. (登録日: 2024-05-01, 公開日: 2024-09-04, 最終更新日: 2024-09-11)

主引用文献

Hartman, J.J.,Hwee, D.T.,Robert-Paganin, J.,Chuang, C.,Chin, E.R.,Edell, S.,Lee, K.H.,Madhvani, R.,Paliwal, P.,Pernier, J.,Sarkar, S.S.,Schaletzky, J.,Schauer, K.,Taheri, K.D.,Wang, J.,Wehri, E.,Wu, Y.,Houdusse, A.,Morgan, B.P.,Malik, F.I.
Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy.
Nat Cardiovasc Res, 3:1003-1016, 2024

PubMed Abstract: Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere resulting in excessive cardiac contractility. The first-in-class cardiac myosin inhibitor, mavacamten, improves symptoms in obstructive HCM. Here we present aficamten, a selective small-molecule inhibitor of cardiac myosin that diminishes ATPase activity by strongly slowing phosphate release, stabilizing a weak actin-binding state. Binding to an allosteric site on the myosin catalytic domain distinct from mavacamten, aficamten prevents the conformational changes necessary to enter the strongly actin-bound force-generating state. In doing so, aficamten reduces the number of functional myosin heads driving sarcomere shortening. The crystal structure of aficamten bound to cardiac myosin in the pre-powerstroke state provides a basis for understanding its selectivity over smooth and fast skeletal muscle. Furthermore, in cardiac myocytes and in mice bearing the hypertrophic R403Q cardiac myosin mutation, aficamten reduces cardiac contractility. Our findings suggest aficamten holds promise as a therapy for HCM.

PubMed: 39196032
DOI: 10.1038/s44161-024-00505-0

実験手法

X-RAY DIFFRACTION (2.33 Å)