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Structural basis for compound C inhibition of the human AMP-activated protein kinase 2 subunit kinase domain

Structural basis for compound C inhibition of the human AMP-activated protein kinase 2 subunit... AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a sensor to maintain energy balance at both the cellular and the whole-body levels and is therefore a potential target for drug design against metabolic syndrome, obesity and type 2 diabetes. Here, the crystal structure of the phosphorylated-state mimic T172D mutant kinase domain from the human AMPK 2 subunit is reported in the apo form and in complex with a selective inhibitor, compound C. The AMPK 2 kinase domain exhibits a typical bilobal kinase fold and exists as a monomer in the crystal. Like the wild-type apo form, the T172D mutant apo form adopts the autoinhibited structure of the `DFG-out' conformation, with the Phe residue of the DFG motif anchored within the putative ATP-binding pocket. Compound C binding dramatically alters the conformation of the activation loop, which adopts an intermediate conformation between DFG-out and DFG-in. This induced fit forms a compound-C binding pocket composed of the N-lobe, the C-lobe and the hinge of the kinase domain. The pocket partially overlaps with the putative ATP-binding pocket. These three-dimensional structures will be useful to guide drug discovery. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Crystallographica Section D: Biological Crystallography International Union of Crystallography

Structural basis for compound C inhibition of the human AMP-activated protein kinase 2 subunit kinase domain

Structural basis for compound C inhibition of the human AMP-activated protein kinase 2 subunit kinase domain

Acta Crystallographica Section D: Biological Crystallography , Volume 67 (5): 480 – Apr 14, 2011

Abstract

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a sensor to maintain energy balance at both the cellular and the whole-body levels and is therefore a potential target for drug design against metabolic syndrome, obesity and type 2 diabetes. Here, the crystal structure of the phosphorylated-state mimic T172D mutant kinase domain from the human AMPK 2 subunit is reported in the apo form and in complex with a selective inhibitor, compound C. The AMPK 2 kinase domain exhibits a typical bilobal kinase fold and exists as a monomer in the crystal. Like the wild-type apo form, the T172D mutant apo form adopts the autoinhibited structure of the `DFG-out' conformation, with the Phe residue of the DFG motif anchored within the putative ATP-binding pocket. Compound C binding dramatically alters the conformation of the activation loop, which adopts an intermediate conformation between DFG-out and DFG-in. This induced fit forms a compound-C binding pocket composed of the N-lobe, the C-lobe and the hinge of the kinase domain. The pocket partially overlaps with the putative ATP-binding pocket. These three-dimensional structures will be useful to guide drug discovery.

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References (53)

Publisher
International Union of Crystallography
Copyright
Copyright (c) 2011 International Union of Crystallography
Subject
AMP-activated protein kinase, metabolic syndrome, drug design, Ser/Thr protein kinases, compound C
ISSN
0907-4449
eISSN
1399-0047
DOI
10.1107/S0907444911010201
pmid
21543851
Publisher site
See Article on Publisher Site

Abstract

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a sensor to maintain energy balance at both the cellular and the whole-body levels and is therefore a potential target for drug design against metabolic syndrome, obesity and type 2 diabetes. Here, the crystal structure of the phosphorylated-state mimic T172D mutant kinase domain from the human AMPK 2 subunit is reported in the apo form and in complex with a selective inhibitor, compound C. The AMPK 2 kinase domain exhibits a typical bilobal kinase fold and exists as a monomer in the crystal. Like the wild-type apo form, the T172D mutant apo form adopts the autoinhibited structure of the `DFG-out' conformation, with the Phe residue of the DFG motif anchored within the putative ATP-binding pocket. Compound C binding dramatically alters the conformation of the activation loop, which adopts an intermediate conformation between DFG-out and DFG-in. This induced fit forms a compound-C binding pocket composed of the N-lobe, the C-lobe and the hinge of the kinase domain. The pocket partially overlaps with the putative ATP-binding pocket. These three-dimensional structures will be useful to guide drug discovery.

Journal

Acta Crystallographica Section D: Biological CrystallographyInternational Union of Crystallography

Published: Apr 14, 2011

Keywords: AMP-activated protein kinase ; metabolic syndrome ; drug design ; Ser/Thr protein kinases ; compound C .

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