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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
11:27

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

Published on: November 2, 2018

Crystal structure of bisphosphorylated IGF-1 receptor kinase: insight into domain movements upon kinase activation

A Pautsch1, A Zoephel, H Ahorn

  • 1Boehringer Ingelheim Pharma KG Deutschland, Birkendorferstrasse 65, D-88400 Biberach, Germany. alexander.pautsch@bc.boehringer-ingelheim.com

Structure (London, England : 1993)
|October 10, 2001
PubMed
Abstract

Insights

The insulin-like growth-factor-1 (IGF-1) receptor kinase structure reveals a novel half-closed conformation. This finding provides a molecular basis for developing targeted cancer therapies by understanding kinase activation mechanisms.

Area of Science:

  • Structural Biology
  • Biochemistry
  • Cancer Research

Background:

  • The insulin-like growth-factor-1 (IGF-1) receptor is a key target in cancer therapy due to its expression in transformed cells.
  • IGF-1 receptor activation involves autophosphorylation and enhanced substrate phosphorylation.
  • Homologous insulin receptor kinase (IRK) structures exist in open (unphosphorylated) and closed (trisphosphorylated) forms.

Purpose of the Study:

  • To determine the crystal structure of the phosphorylated IGF-1 receptor protein tyrosine kinase domain.
  • To elucidate the conformational states of the IGF-1 receptor kinase during activation.

Main Methods:

  • X-ray crystallography was used to determine the 2.1 Å crystal structure of the IGF-1 receptor protein tyrosine kinase domain (IGF-1RK2P) bound to an ATP analog.
  • Analysis of domain movements and conformational changes.

Main Results:

  • The determined structure revealed IGF-1RK2P in a previously unobserved, half-closed conformation.
  • The activation loop was partially disordered, and the bound ligand was not in a phosphoryl transfer-compatible conformation.
  • Domain movements were characterized by two orthogonal rotational components.

Conclusions:

  • Kinase activation involves conformational changes dependent on phosphorylation levels and activation loop conformation.
  • The determined IGF-1RK structure offers a molecular foundation for designing selective anti-cancer drugs.

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