WEHI Special Structural Biology Seminar hosted by Professor Michael Lawrence
 

Michael A. Weiss

Robert Harris Professor of Biochemistry & Molecular Biology; Chair, Dept of Biochemistry & Molecular Biology and Director, PHI Center for Chemical Biology

Design and Operation of a Glucose-Responsive Insulin

Davis Auditorium – please use side entrance

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Including Q&A session

Mike Weiss, received his M.D. from the Harvard Medical School/MIT Program in Health Sciences & Technology in 1986 and Ph.D. in Biophysics from Harvard University in 1986. He is currently the chair of the Department of Biochemistry and Molecular Biology at Indiana University School of Medicine. His research has focused on (a) the molecular genetics of neonatal diabetes mellitus and (b) the molecular genetics of intersexual abnormalities of the newborn. Each of these interests integrates structural approaches with functional studies of clinical mutations causing developmental disorders. Dr. Weiss also has maintained a long-term interest in the structure and function of insulin with broad implications for hormone biosynthesis and function. The Weiss laboratory was the first to decipher the solution structures of insulin and proinsulin. Landmark collaborative structures of insulin/receptor complexes (with WEHI) have recently revealed how insulin engage its receptor. For this body of work and its translational implications, Dr. Weiss was awarded the JDRF Grodsky Award in basic science related to Type 1 diabetes mellitus (2/2020). His recent election as an AAAS Fellow referenced both contributions in molecular endocrinology to mechanisms of insulin action and gonadogenesis (1/2022).  

Binding of insulin to the insulin receptor is associated with conformational changes in both partners. How might these structural insights be exploited to enhance the treatment of diabetes mellitus (DM) and health-care outcomes? Here, we describe the mechanism-based design and function of a unimolecular glucose-responsive insulin (GRI). This program of research was motivated by the acute and chronic sequellae of recurrent hypoglycemia in the management of DM, including progressive cognitive decline and shortened life span. The mechanism of glucose-responsiveness recapitulates the native molecular basis of hormone-receptor binding and activation: a transition between closed and open states of insulin. Functional validation was obtained in cell-based studies and corroborated in rats via hypoglycemic-, euglycemic- and hyperglycemic clamps. Proof of molecular mechanism was provided by cryo-EM visualization of the hormone-receptor ectodomain complexes in the absence (non-signaling) or presence (signaling) of glucose; these studies were formed in collaboration with Prof. M.C. Lawrence, Drs. Y. Xu and H. Venugopal (Melbourne, AU). A novel inactive transition state of the hormone-ectodomain complex was observed in which the GRI is bound to the “legs” of the receptor (Site 2) with incomplete formation of Site 1 and without full conversion to the active signaling conformation. Extrapolation of the rat data to human physiology and pharmacology predicts marked protection from moderate and severe hypoglycemic episodes in a therapeutic regimen of tight glycemic control. “In silico” clinical trials (undertaken in collaboration with Prof. M. Strano at MIT) further suggest that aggressive glycemic targets may be achieved without elevated risk of hypoglycemia. 

All welcome!