Journal article
Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding
MD Glidden, Y Yang, NA Smith, NB Phillips, K Carr, NP Wickramasinghe, F Ismail-Beigi, MC Lawrence, BJ Smith, MA Weiss
Journal of Biological Chemistry | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Published : 2018
Abstract
Domain-minimized insulin receptors (IRs) have enabled crystallographic analysis of insulin-bound "micro-receptors." In manuscript. such structures, the C-terminal segment of the insulin B chain inserts between conserved IR domains, unmasking an invariant receptor-binding surface that spans both insulinAand B chains. This "open" conformation not only rationalizes the inactivity of single-chain insulin (SCI) analogs (in which the A and B chains are directly linked), but also suggests that connecting (C) domains of sufficient length will bind the IR. Here, we report the high-resolution solution structure and dynamics of such an active SCI. The hormone's closed-to-open transition is foreshadowed..
View full abstractGrants
Awarded by Cooperative Research Centres, Australian Government Department of Industry
Funding Acknowledgements
This work, a contribution of the Cleveland Center for Membrane and Structural Biology and CWRU Institute for the Science of Origins, was supported in part by National Institutes of Health Grants R01 DK040949 and R01 DK069764 (to M. A. W.), by Australian National Health and Medical Research Council Project Grant APP1058233 (to M. C. L.), Victorian State Government Operational Infrastructure Support, Australian NHMRC Independent Research Institutes Infrastructure Support Scheme, both to his institution, and by the National Computational Infrastructure (NCI), which is supported by the Australian Government. This work was also supported by an Australian Government Research Training Program Scholarship (to N. A. S.). M. A. W. has equity in Thermalin Diabetes, LLC (Cleveland, OH), where he serves as Chief Innovation Officer; he has also been a consultant to Merck Research Laboratories and DEKA Research & Development Corp. N. B. P. and F. I.-B. are consultants to Thermalin Diabetes, LLC. Part of M.C.L.'s research is funded by Sanofi (Germany). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Pre-doctoral Fellow of the National Institutes of Health supported by Medical Scientist Training Program 5T32GM007250-38 and Fellowship 1F30DK104618-01.Supported in part by American Diabetes Association Grants 7-13-IN-31 and 1-08-RA-149.