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6bm7
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of Trypanosoma brucei AdoMetDC/prozyme heterodimer in complex with pyrimidineamine inhibitor UTSAM568== | |
| + | <StructureSection load='6bm7' size='340' side='right' caption='[[6bm7]], [[Resolution|resolution]] 2.98Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6bm7]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BM7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BM7 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B3P:2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>B3P</scene>, <scene name='pdbligand=DY7:2-amino-4-[(3,5-dibromophenyl)amino]-6-methylpyrimidin-1-ium'>DY7</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=PUT:1,4-DIAMINOBUTANE'>PUT</scene></td></tr> | ||
| + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PYR:PYRUVIC+ACID'>PYR</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Adenosylmethionine_decarboxylase Adenosylmethionine decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.50 4.1.1.50] </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=6bm7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bm7 OCA], [http://pdbe.org/6bm7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bm7 RCSB], [http://www.ebi.ac.uk/pdbsum/6bm7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bm7 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/DCAMP_TRYBB DCAMP_TRYBB]] Probably has no catalytic activity due to the loss of several residues required for processing and catalysis (PubMed:17485680). Forms a complex with S-adenosylmethionine decarboxylase AdoMetDC which is essential to activate AdoMetDC (PubMed:17485680, PubMed:18949025). Required for the biosynthesis of the polyamine spermidine (PubMed:18949025). Required for growth and survival during the bloodstream life cycle stage (PubMed:18949025).<ref>PMID:17485680</ref> <ref>PMID:18949025</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chemistry program elucidated structure-activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization. | ||
| - | + | Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase.,Volkov OA, Brockway AJ, Wring SA, Peel M, Chen Z, Phillips MA, De Brabander JK J Med Chem. 2017 Dec 22. doi: 10.1021/acs.jmedchem.7b01654. PMID:29271204<ref>PMID:29271204</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6bm7" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Adenosylmethionine decarboxylase]] | ||
| + | [[Category: Chen, Z]] | ||
| + | [[Category: Phillips, M A]] | ||
| + | [[Category: Volkov, O A]] | ||
| + | [[Category: Adometdc]] | ||
| + | [[Category: Decarboxylase]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Lyase-lyase inhibitor complex]] | ||
| + | [[Category: Prozyme]] | ||
| + | [[Category: Trypanosoma]] | ||
Revision as of 05:51, 3 January 2018
Crystal structure of Trypanosoma brucei AdoMetDC/prozyme heterodimer in complex with pyrimidineamine inhibitor UTSAM568
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