skip to main content

Title: Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex

[AsnB26]- and [GlyB26]-insulin mutants attain a B26-turn like fold without assistance of chemical modifications. Their structures match the insulin receptor interface and expand the spectrum of insulin conformations. The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.
Authors:
; ; ;  [1] ; ;  [2] ;  [1] ;  [2] ;  [3]
  1. Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic)
  2. The University of York, Heslington, York YO10 5DD (United Kingdom)
  3. (Czech Republic)
Publication Date:
OSTI Identifier:
22347759
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 70; Journal Issue: Pt 10; Other Information: PMCID: PMC4188015; PMID: 25286859; PUBLISHER-ID: dz5340; OAI: oai:pubmedcentral.nih.gov:4188015; Copyright (c) Žáková et al. 2014; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; COMPLEXES; INTERACTIONS; INTERFACES; MODIFICATIONS; MOLECULAR DYNAMICS METHOD; ORIGIN; RECEPTORS; SPECIFICITY; SPECTRA