Journal article
Contribution of tyrb26to the function and stability of insulin structure-activity relationships at a conserved hormone-receptor interface
V Pandyarajan, NB Phillips, N Rege, MC Lawrence, J Whittaker, MA Weiss
Journal of Biological Chemistry | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Published : 2016
Open access
Abstract
Crystallographic studies of insulin bound to receptor domains have defined the primary hormone-receptor interface. We investigated the role of TyrB26 , a conserved aromatic residue at this interface. To probe the evolutionary basis for such conservation, we constructed 18 variants at B26. Surprisingly, nonaromatic polar or charged side chains (such as Glu, Ser, or ornithine (Orn)) conferred high activity, whereas the weakestbinding analogs contained Val, Ile, and Leu substitutions. Modeling of variant complexes suggested that the B26 side chains pack within a shallow depression at the solvent-exposed periphery of the interface. This interface would disfavor large aliphatic side chains. The a..
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Funding Acknowledgements
This work was supported in part by National Institutes of Health Grants R01 DK040949 and DK079233 (NIDDK; to M. A. W.). This work was also supported by Australian National Health and Medical Research Council (NHMRC) Project Grants 1005896 and 1058233 and the Hazel and Pip Appel Fund (to M. C. L.). M. A. W. has equity in Thermalin Diabetes, LLC (Cleveland, OH), where he serves as Chief Scientific Officer. He has also been a consultant to Merck Research Laboratories and DEKA Research and Development Corp. N. B. P. and J. W. are consultants to Thermalin Diabetes, LLC. Part of M. C. L.'s research was 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.r Supported by a predoctoral fellowship of the Case Western Reserve University Medical Scientist Training Program supported by National Institutes of Health (NIH) Grant T32 GM007250 and individual NIH Fellowship F30 DK094685-04 from the NIDDK.r Supported in part by the American Diabetes Association.r Recipient of National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme Grant 361646 and Victorian State Government Operational Infrastructure Support Grant (to the Walter and Eliza Hall Institute).