Structure and dynamics of the insulin receptor: implications for receptor activation and drug discovery

Libin Ye, Suvrajit Maji, Narinder Sanghera, Piraveen Gopalasingam, Evgeniy Gorbunov, Sergey Tarasov, Oleg Epstein, Judith Klein-Seetharaman

Research output: Contribution to journalReview articlepeer-review

15 Scopus citations

Abstract

Recently, major progress has been made in uncovering the mechanisms of how insulin engages its receptor and modulates downstream signal transduction. Here, we present in detail the current structural knowledge surrounding the individual components of the complex, binding sites, and dynamics during the activation process. A novel kinase triggering mechanism, the ‘bow-arrow model’, is proposed based on current knowledge and computational simulations of this system, in which insulin, after its initial interaction with binding site 1, engages with site 2 between the fibronectin type III (FnIII)-1 and -2 domains, which changes the conformation of FnIII-3 and eventually translates into structural changes across the membrane. This model provides a new perspective on the process of insulin binding to its receptor and, thus, could lead to future novel drug discovery efforts.

Original languageEnglish (US)
Pages (from-to)1092-1102
Number of pages11
JournalDrug discovery today
Volume22
Issue number7
DOIs
StatePublished - Jul 2017
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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