Journal article

How insulin engages its primary binding site on the insulin receptor

John G Menting, Jonathan Whittaker, Mai B Margetts, Linda J Whittaker, Geoffrey K-W Kong, Brian J Smith, Christopher J Watson, Lenka Zakova, Emilia Kletvikova, Jiri Jiracek, Shu Jin Chan, Donald F Steiner, Guy G Dodson, Andrzej M Brzozowski, Michael A Weiss, Colin W Ward, Michael C Lawrence

NATURE | NATURE PUBLISHING GROUP | Published : 2013

Abstract

Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin-insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin wit..

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University of Melbourne Researchers

Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by NHMRC


Awarded by NIH


Awarded by American Diabetes Association


Awarded by Grant Agency of the Czech Republic


Awarded by Research Project of the Academy of Sciences of the Czech Republic


Awarded by NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES


Awarded by NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES


Funding Acknowledgements

This Letter is dedicated to our co-author, the late Guy Dodson, in recognition of his lifetime contribution to the study of the structure of insulin. This work was supported by Australian National Health and Medical Research Council (NHMRC) Project grants 516729, 575539 and 1005896 and the Hazel and Pip Appel Fund (to M. C. L.), NHMRC Independent Research Institutes Infrastructure Support Scheme Grant 361646 and Victorian State Government Operational Infrastructure Support Grant (to the Walter and Eliza Hall Institute of Medical Research), NIH grant no. DK40949(to M. A. W. and J.W.) and American Diabetes Association grant no. 1-11INI-31 (to J.W.), Grant Agency of the Czech Republic grant P207/11/P430 (to L.Z.), Research Project of the Academy of Sciences of the Czech Republic RVO: 61388963 (to the Institute of Organic Chemistry and Biochemistry), NIH grants DK13914 and DK20595 (to D. F. S.), a BBSRC PhD studentship (to C. J.W.) and the UoY Research Priming Fund(to the York Structural Biology Laboratory). Part of this research was undertaken on the MX2 beamline at the Australian Synchrotron (AS), Victoria, Australia. We thank the DLS for access to beamline I24 and the Australian International Synchrotron Access Program for travel funds. We thank P. Colman and J. Gulbis, our colleagues at CSIRO and the AS beam line staff for their support; J. Turkenburg for assistance in collecting data at DLS; K. Huang for assistance with midi-receptor photo-crosslinking; Q.-X. Hua and Y. Yang for discussion of NMR studies of insulin; S.-Q. Hu, S. H. Nakagawa, N. F. Phillips and S. Wang for assistance with insulin analogue synthesis; P. G. Katsoyannis for advice about the synthesis of photo-reactive insulin analogues and for providing an initial set of Pap analogues; K. Siddle for supplying the 83-7 and 83-14 hybridomas; L. Lu and the fermentation group CSIRO Materials Science and Engineering for large-scale cell culture.