View source for 4cfe


==Structure of full length human AMPK in complex with a small molecule activator, a benzimidazole derivative (991)==
<StructureSection load='4cfe' size='340' side='right'caption='[[4cfe]], [[Resolution|resolution]] 3.02&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4cfe]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CFE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CFE FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.023&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=992:5-[[6-CHLORANYL-5-(1-METHYLINDOL-5-YL)-1H-BENZIMIDAZOL-2-YL]OXY]-2-METHYL-BENZOIC+ACID'>992</scene>, <scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=STU:STAUROSPORINE'>STU</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4cfe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cfe OCA], [https://pdbe.org/4cfe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cfe RCSB], [https://www.ebi.ac.uk/pdbsum/4cfe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cfe ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AAKB1_HUMAN AAKB1_HUMAN] Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3).
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== Publication Abstract from PubMed ==
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.

Structural basis of AMPK regulation by small molecule activators.,Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S, Giordanetto F, Martin SR, Carling D, Gamblin SJ Nat Commun. 2013 Dec 19;4:3017. doi: 10.1038/ncomms4017. PMID:24352254<ref>PMID:24352254</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4cfe" style="background-color:#fffaf0;"></div>

==See Also==
*[[AMP-activated protein kinase 3D structures|AMP-activated protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bright NJ]]
[[Category: Carling D]]
[[Category: Carmena D]]
[[Category: Gamblin SJ]]
[[Category: Giordanetto F]]
[[Category: Haire LF]]
[[Category: Hallen S]]
[[Category: Heath RB]]
[[Category: Martin SR]]
[[Category: Patel BR]]
[[Category: Sanders MJ]]
[[Category: Underwood E]]
[[Category: Walker PA]]
[[Category: Xiao B]]