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Membranes 2014, 4(4), 730-746; doi:10.3390/membranes4040730

Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound Microreceptor

Department of Chemical Engineering, University of New Hampshire, 33 Academic Way, Durham,NH 03824, USA
Received: 18 August 2014 / Revised: 18 September 2014 / Accepted: 5 October 2014 / Published: 10 October 2014
(This article belongs to the Special Issue Structure and Function of Membrane Receptors)
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Abstract

Insulin binding to the insulin receptor (IR) is the first key step in initiating downstream signaling cascades for glucose homeostasis in higher organisms. The molecular details of insulin recognition by IR are not yet completely understood, but a picture of hormone/receptor interactions at one of the epitopes (Site 1) is beginning to emerge from recent structural evidence. However, insulin-bound structures of truncated IR suggest that crystallographic conformation of insulin cannot be accommodated in the full IR ectodomain due to steric overlap of insulin with the first two type III fibronectin domains (F1 and F2), which are contributed to the insulin binding-pocket by the second subunit in the IR homodimer. A conformational change in the F1-F2 pair has thus been suggested. In this work, we present an all-atom structural model of complex of insulin and the IR ectodomain, where no structural overlap of insulin with the receptor domains (F1 and F2) is observed. This structural model was arrived at by flexibly fitting parts of our earlier insulin/IR all-atom model into the simulated density maps of crystallized constructs combined with conformational sampling from apo-IR solution conformations. Importantly, our experimentally-consistent model helps rationalize yet unresolved Site View Full-Text
Keywords: insulin; insulin receptor; receptor tyrosine kinases; membrane receptors; docking; molecular dynamics simulations; signal transduction insulin; insulin receptor; receptor tyrosine kinases; membrane receptors; docking; molecular dynamics simulations; signal transduction
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Vashisth, H. Flexibility in the Insulin Receptor Ectodomain Enables Docking of Insulin in Crystallographic Conformation Observed in a Hormone-Bound Microreceptor. Membranes 2014, 4, 730-746.

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