5bwu
From Proteopedia
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| - | ''' | + | ==X-RAY CRYSTAL STRUCTURE AT 2.17A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE (BCATM) COMPLEXED WITH A TRIAZOLOPYRIMIDINONE COMPOUND AND AN INTERNAL ALDIMINE LINKED PLP COFACTOR.== |
| + | <StructureSection load='5bwu' size='340' side='right' caption='[[5bwu]], [[Resolution|resolution]] 2.17Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5bwu]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BWU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BWU FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4VR:2-[(4-BROMOBENZYL)AMINO]-5-PROPYL[1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7(4H)-ONE'>4VR</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5bwr|5bwr]], [[5bwt|5bwt]]</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Branched-chain-amino-acid_transaminase Branched-chain-amino-acid transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.42 2.6.1.42] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5bwu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bwu OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5bwu RCSB], [http://www.ebi.ac.uk/pdbsum/5bwu PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/BCAT2_HUMAN BCAT2_HUMAN]] Catalyzes the first reaction in the catabolism of the essential branched chain amino acids leucine, isoleucine, and valine. May also function as a transporter of branched chain alpha-keto acids. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The hybridisation of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm), based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimisation of activity with maintenance of ligand efficiency, whilst the focus on physical properties delivered compounds with excellent pharmacokinetic exposure that enabled an acute proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]p yrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine and valine in this acute study. | ||
| - | The | + | The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridising fragment and HTS hits.,Bertrand SM, Ancellin N, Beaufils B, Bingham RP, Borthwick JA, Boullay AB, Boursier E, Carter PS, Chung CW, Churcher I, Dodic N, Fouchet MH, Fournier C, Francis P, Gummer LA, Herry K, Hobbs A, Hobbs CI, Homes P, Jamieson C, Nicodeme E, Pickett SD, Reid IH, Simpson GL, Sloan LA, Smith SE, Somers DO, Spitzfaden C, Suckling CJ, Valko K, Washio Y, Young RJ J Med Chem. 2015 Jun 19. PMID:26090771<ref>PMID:26090771</ref> |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| + | </StructureSection> | ||
| + | [[Category: Branched-chain-amino-acid transaminase]] | ||
| + | [[Category: SOMERS, D O]] | ||
| + | [[Category: Fold type iv]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 12:06, 1 July 2015
X-RAY CRYSTAL STRUCTURE AT 2.17A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE (BCATM) COMPLEXED WITH A TRIAZOLOPYRIMIDINONE COMPOUND AND AN INTERNAL ALDIMINE LINKED PLP COFACTOR.
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