4CFF: Structure Of Full Length Human Ampk In Complex With A Small Molecule Activator, A Thienopyridone Derivative (a-769662)

Citation:
Abstract
AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases in AMP/ADP concentration relative to ATP. Binding of AMP causes allosteric activation of the enzyme and binding of either AMP or ADP promotes and maintains the phosphorylation of threonine 172 within the activation loop of the kinase. AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases including type 2 diabetes and, more recently, cancer. A number of direct AMPK activators have been reported as having beneficial effects in treating metabolic diseases, but there has been no structural basis for activator binding to AMPK. Here we present the crystal structure of human AMPK in complex with a small molecule activator that binds at a site between the kinase domain and the carbohydrate-binding module, stabilising the interaction between these two components. The nature of the activator-binding pocket suggests the involvement of an additional, as yet unidentified, metabolite in the physiological regulation of AMPK. Importantly, the structure offers new opportunities for the design of small molecule activators of AMPK for treatment of metabolic disorders.
PDB ID: 4CFFDownload
MMDB ID: 116201
PDB Deposition Date: 2013/11/14
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 3.92  Å
Source Organism:
Similar Structures:
Biological Unit for 4CFF: trimeric; determined by author and by software (PISA)
Molecular Components in 4CFF
Label Count Molecule
Proteins (3 molecules)
1
5'-amp-activated Protein Kinase Catalytic Subunit Alpha-2(Gene symbol: PRKAA2)
Molecule annotation
1
5'-amp-activated Protein Kinase Subunit Beta-1(Gene symbol: PRKAB1)
Molecule annotation
1
5'-amp-activated Protein Kinase Subunit Gamma-1(Gene symbol: PRKAG1)
Molecule annotation
Chemicals (4 molecules)
1
1
2
1
3
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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