Journal article
The signalling conformation of the insulin receptor ectodomain
F Weis, JG Menting, MB Margetts, SJ Chan, Y Xu, N Tennagels, P Wohlfart, T Langer, CW Müller, MK Dreyer, MC Lawrence
Nature Communications | NATURE PUBLISHING GROUP | Published : 2018
Abstract
Understanding the structural biology of the insulin receptor and how it signals is of key importance in the development of insulin analogs to treat diabetes. We report here a cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation. The resolution of the cryo-electron microscopy maps is 3.2 Å in the insulin-binding region and 4.2 Å in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to ..
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Awarded by National Institutes of Health
Funding Acknowledgements
M.C.L. acknowledges financial support from the Australian National Health and Medical Research Council (NHMRC) Project Grants APP1099595 and APP1128553; his Institute receives Victorian State Government Operational Infrastructure Support and funding from the Australian NHMRC Independent Research Institutes Infrastructure Support Scheme. S.J.C. acknowledges financial support from the National Institutes of Health grants DK013914 and UC DRTC DK020595. We thank Mr John Bentley (CSIRO, Australia) for assistance with the preparation of the bis-BOC-insulin-affinity resin, Mr Peter Hoyne (CSIRO, Australia) for advice regarding the production of IR Delta beta-zip, and Prof. Ken Siddle (University of Cambridge, England) for providing the hybridomas expressing mAb 83-7. This manuscript is dedicated to our late colleagues Dr Colin Ward and Professor Donald Steiner, who instigated independent aspects of the work described here.