Omecamtiv Mecarbil binds in a narrow cleft separating the N-terminal 25-K domain from the lower 50-K domain of the human β-cardiac motor domain, inducing allosteric changes that tune motor activity.
Does Omecamtiv Mecarbil alter the structural conformation and kinetic activity of human β-cardiac myosin motor domain?
Omecamtiv mecarbil binds to a specific cleft in the human β-cardiac myosin motor domain, inducing allosteric changes that explain its kinetic and mechanical tuning of cardiac myosin.
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.
Winkelmann et al. (Thu,) conducted a other in Systolic heart failure (contextual). Omecamtiv Mecarbil vs. Apo structure (drug-free) was evaluated on Crystal structure and motor activity (unloaded shortening velocity and ATPase activity). Omecamtiv Mecarbil binds in a narrow cleft separating the N-terminal 25-K domain from the lower 50-K domain of the human β-cardiac motor domain, inducing allosteric changes that tune motor activity.
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