Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
How insulin binds: structure of a micro-receptor complex and implications for analog design
The discovery of insulin in 1921 represented a landmark in molecular medicine and led to extensive investigation of the structure and function of this globular protein hormone with application to therapeutic analog design. This presentation provides a summary of the current structural understanding of the active conformation of insulin in relation to its mechanism of receptor binding. Implications of recent crystal structures and NMR studies will be discussed as a foundation for the engineering of novel ultra-stable single-chain analogs, intended as basal (long-acting) insulin formulations for use in regions of the developing world lacking access to refrigeration. Prospects will be envisaged for the extension of such protein technology to implantable intra-peritoneal insulin pumps whose present use is complicated by degradation of the hormone at body temperature on a time scale of 1-3 months.
A key constraint in the design of therapeutic insulin analogs is posed by their physical degradation to form amyloid. Spectroscopic studies of insulin fibrils has provided structural constraints regarding the molecular structure of a protofilament and distorted conformations of insulin proposed as intermediates in the process of fibrillation. Consideration of such constraints has highlighted the potential utility of single-chain insulin analogs containing foreshortened connection domains. Such foreshortened tethers must accommodate inducted fit of the hormone on receptor binding, a binding mechanism that entails splaying of the C-terminal segment of the B chain. Insight into the hormone-binding surfaces of the ectodomain of the insulin receptor and "micro-receptor" models of the hormone-receptor complex have enabled visualization at low resolution of how the splayed B chain inserts between domains of the receptor. These recent structures provide a new and promising foundation for analysis of structure-activity relationships with direct application to the design of novel insulin analogs. Efforts are underway toward the optimization of insulin analogs to address unmet needs of patients with diabetes mellitus in affluent societies and in the developing world.
This work was supported in part by the National Institutes of Health and the Leona M. and Harry B. Helmsley Foundation. Collaborative ties with V. Chauhan, F. Ismail-Beigi, S.B. Kent, M. Lawrence, J. Menting, N. Phillips, D. F. Steiner (deceased), R. Tycko, C. Ward, J. Whittaker, N. Wickramasinghe and Y. Yang are gratefully acknowledged.
Menting, J.G., Yang, Y., Chan, S.-J., Phillips, N.B., Smith, B.J., Whittaker, J., Wickramasinghe, N.P., Whittaker, L., Pandyarajan, V., Wan, Z.-l., Yadav, S.P., Carroll, J.M., Strokes, N., Roberts, Jr., C. T., Ismail-Beigi. F., Milewski, M., Donald F. Steiner, D.F., Chauhan, V.C., Ward, C.W., Weiss, M.A., & Michael C. Lawrence, M.C. (2014) Proc. Natl. Acad. Sci. USA. (PNAS-Plus) 111, E3395-404.
Michael A. Weiss
Department of Biochemistry