Monday, April 18, at 12:10 p.m. in CUE 419
Donald A. Winkelmann, Professor of Pathology and Laboratory Medicine,
Robert Wood Johnson, Medical School, Rutgers University
Dr. Winkelmann received his doctorate at the University of Wisconsin Madison in Biochemistry in 1980 working on bacterial ribosome structure. He completed his postdoctoral training with Susan Lowey in the structural biology laboratory of the Rosenstiel Center at Brandeis University. It was at Brandeis where he began his work on the structure of striated muscle myosin an initiated a collaboration that led to the solving the structure of the first molecular motor. He moved to a faculty position in the department of Pathology of the Robert Wood Johnson Medical School where he has continued his work on striated muscle in the area of the cellular regulation of the folding, assembly and maintenance of striated muscle myosin; a process that is essential to adaptation of sarcomeres to physiological changes. These studies lead to the development of an expression system for production of human -cardiac myosin and the determination of the structure of the cardiac myosin motor domain in association with a cardiac specific myosin allosteric activator. This discovery forms the basis for future work on the pharmacological treatment of cardiomyopathies.
Structural basis of allosteric control of cardiac myosin by Omecamtiv Mecarbil
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 toward products leading to a faster transition from weak to strong actin bound states. The structure of the human -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 key residues that couple lever arm movement to the nucleotide state. In addition, OM induces allosteric changes in three strands of the -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.
