5bwr
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 5bwr is ON HOLD Authors: SOMERS, D. Description: X-RAY CRYSTAL STRUCTURE AT 2.20A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==X-RAY CRYSTAL STRUCTURE AT 2.20A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE (BCATM) COMPLEXED WITH A PYRAZOLOPYRIMIDINONE FRAGMENT AND AN INTERNAL ALDIMINE LINKED PLP.== | |
| + | <StructureSection load='5bwr' size='340' side='right'caption='[[5bwr]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5bwr]] is a 2 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=5BWR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BWR 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]] 2.2Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4VT:5-BENZYL-7-OXO-4,7-DIHYDROPYRAZOLO[1,5-A]PYRIMIDINE-3-CARBONITRILE'>4VT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</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=5bwr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bwr OCA], [https://pdbe.org/5bwr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bwr RCSB], [https://www.ebi.ac.uk/pdbsum/5bwr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bwr ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://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 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> | |
| - | [[Category: | + | </div> |
| - | [[Category: Somers | + | <div class="pdbe-citations 5bwr" style="background-color:#fffaf0;"></div> |
| + | |||
| + | ==See Also== | ||
| + | *[[Aminotransferase 3D structures|Aminotransferase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Somers D]] | ||
Current revision
X-RAY CRYSTAL STRUCTURE AT 2.20A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE (BCATM) COMPLEXED WITH A PYRAZOLOPYRIMIDINONE FRAGMENT AND AN INTERNAL ALDIMINE LINKED PLP.
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