4PA0

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

Summary for 4PA0

• Entry DOI: 10.2210/pdb4pa0/pdb
• Related: 4P7H
• Descriptor: 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)
• Functional Keywords: cardiac, myosin, motor, omecamtiv mercarbil, motor-fluorescent protein complex, motor/fluorescent protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 234298.78

Authors

Winkelmann, D.A.,Miller, M.T.,Stock, A.M. (deposition date: 2014-04-06, release date: 2015-07-08, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.25 Å)