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The structure of human GCN2 reveals a parallel, back-to-back kinase dimer with a plastic DFG activation loop motif

DOI: 10.1042/BCJ20190196 DOI Help

Authors: Taiana Maia De Oliveira (AstraZeneca) , Victoria Korboukh (AstraZeneca) , Sarah Caswell (AstraZeneca) , Jon J. Winter Holt (AstraZeneca) , Michelle Lamb (AstraZeneca) , Alexander W. Hird (AstraZeneca) , Ross Overman (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Biochemical Journal , VOL 477 , PAGES 275 - 284

State: Published (Approved)
Published: January 2020

Open Access Open Access

Abstract: When activated by amino acid starvation, the stress sensing protein kinase GCN2 phosphorylates the eukaryotic initiation factor 2 alpha, inhibiting translation to conserve energy and facilitate cell survival. Amino acid starvation, particularly of tryptophan and arginine, affects immune tolerance by suppressing differentiation and proliferation of T-cells via activation of GCN2 kinase. In addition, the GCN2 pathway mediates cancer survival directly within the context of metabolic stress. Here, we report the first crystal structures of the human GCN2 kinase domain (KD) in complex with two inhibitors of different size, shape, and chemical scaffold. Three novel activation loop conformations representative of different activation states of the kinase are described. In addition, a novel dimerization organization for GCN2 is observed. This arrangement is consistent with the hypothesis that the GCN2 KD forms an antiparallel inactive dimer until uncharged tRNA binds to it and triggers conformational changes that shift the equilibrium to the active parallel dimer.

Journal Keywords: GCN2; kinase; x-ray structure

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 04/05/2022 11:36

Documents:
bcj-2019-0196.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)