4PA0

Omecamtiv Mercarbil binding site on the Human Beta-Cardiac Myosin Motor Domain

4PA0 の概要

• エントリーDOI: 10.2210/pdb4pa0/pdb
• 関連するPDBエントリー: 4P7H
• 分子名称: Myosin-7,Green fluorescent protein, methyl 4-(2-fluoro-3-{[(6-methylpyridin-3-yl)carbamoyl]amino}benzyl)piperazine-1-carboxylate, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: cardiac, myosin, motor, omecamtiv mercarbil, motor-fluorescent protein complex, motor/fluorescent protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 234298.78

構造登録者

Winkelmann, D.A.,Miller, M.T.,Stock, A.M. (登録日: 2014-04-06, 公開日: 2015-07-08, 最終更新日: 2024-10-16)

主引用文献

Winkelmann, D.A.,Forgacs, E.,Miller, M.T.,Stock, A.M.
Structural basis for drug-induced allosteric changes to human beta-cardiac myosin motor activity.
Nat Commun, 6:7974-7974, 2015

PubMed 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.

PubMed: 26246073
DOI: 10.1038/ncomms8974

実験手法

X-RAY DIFFRACTION (2.25 Å)