How ligand binds to the type 1 insulin-like growth factor receptor.

Abstract:

:Human type 1 insulin-like growth factor receptor is a homodimeric receptor tyrosine kinase that signals into pathways directing normal cellular growth, differentiation and proliferation, with aberrant signalling implicated in cancer. Insulin-like growth factor binding is understood to relax conformational restraints within the homodimer, initiating transphosphorylation of the tyrosine kinase domains. However, no three-dimensional structures exist for the receptor ectodomain to inform atomic-level understanding of these events. Here, we present crystal structures of the ectodomain in apo form and in complex with insulin-like growth factor I, the latter obtained by crystal soaking. These structures not only provide a wealth of detail of the growth factor interaction with the receptor's primary ligand-binding site but also indicate that ligand binding separates receptor domains by a mechanism of induced fit. Our findings are of importance to the design of agents targeting IGF-1R and its partner protein, the human insulin receptor.

journal_name

Nat Commun

journal_title

Nature communications

authors

Xu Y,Kong GK,Menting JG,Margetts MB,Delaine CA,Jenkin LM,Kiselyov VV,De Meyts P,Forbes BE,Lawrence MC

doi

10.1038/s41467-018-03219-7

subject

Has Abstract

pub_date

2018-02-26 00:00:00

pages

821

issue

1

issn

2041-1723

pii

10.1038/s41467-018-03219-7

journal_volume

9

pub_type

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