6scz
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Mycobacterium tuberculosis alanine racemase inhibited by DCS== | |
| + | <StructureSection load='6scz' size='340' side='right'caption='[[6scz]], [[Resolution|resolution]] 1.57Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6scz]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SCZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6SCZ FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=L7N:(~{E})-[2-methyl-3-oxidanyl-5-(phosphonooxymethyl)pyridin-4-yl]methylidene-[(4~{R})-3-oxidanylidene-1,2-oxazolidin-4-yl]azanium'>L7N</scene>, <scene name='pdbligand=OJQ:[2-methyl-3-oxidanyl-5-(phosphonooxymethyl)pyridin-4-yl]methyl-(3-oxidanyl-1,2-oxazol-4-yl)azanium'>OJQ</scene>, <scene name='pdbligand=P4K:polyethylene+glycol'>P4K</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Alanine_racemase Alanine racemase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.1.1.1 5.1.1.1] </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=6scz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6scz OCA], [http://pdbe.org/6scz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6scz RCSB], [http://www.ebi.ac.uk/pdbsum/6scz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6scz ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/ALR_MYCTU ALR_MYCTU]] Catalyzes the interconversion of L-alanine and D-alanine.<ref>PMID:11267762</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The broad-spectrum antibiotic D-cycloserine (DCS) is a key component of regimens used to treat multi- and extensively drug-resistant tuberculosis. DCS, a structural analog of D-alanine, binds to and inactivates two essential enzymes involved in peptidoglycan biosynthesis, alanine racemase (Alr) and D-Ala:D-Ala ligase. Inactivation of Alr is thought to proceed via a mechanism-based irreversible route, forming an adduct with the pyridoxal 5'-phosphate cofactor, leading to bacterial death. Inconsistent with this hypothesis, Mycobacterium tuberculosis Alr activity can be detected after exposure to clinically relevant DCS concentrations. To address this paradox, we investigated the chemical mechanism of Alr inhibition by DCS. Inhibition of M. tuberculosis Alr and other Alrs is reversible, mechanistically revealed by a previously unidentified DCS-adduct hydrolysis. Dissociation and subsequent rearrangement to a stable substituted oxime explains Alr reactivation in the cellular milieu. This knowledge provides a novel route for discovery of improved Alr inhibitors against M. tuberculosis and other bacteria. | ||
| - | + | D-Cycloserine destruction by alanine racemase and the limit of irreversible inhibition.,de Chiara C, Homsak M, Prosser GA, Douglas HL, Garza-Garcia A, Kelly G, Purkiss AG, Tate EW, de Carvalho LPS Nat Chem Biol. 2020 Mar 16. pii: 10.1038/s41589-020-0498-9. doi:, 10.1038/s41589-020-0498-9. PMID:32203411<ref>PMID:32203411</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6scz" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Alanine racemase]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Carvalho, L P.S de]] | ||
| + | [[Category: Chiara, C de]] | ||
| + | [[Category: Homsak, M]] | ||
| + | [[Category: Prosser, G]] | ||
| + | [[Category: Purkiss, A]] | ||
| + | [[Category: Enzyme]] | ||
| + | [[Category: Isomerase]] | ||
| + | [[Category: Peptidoglycan biosynthesis]] | ||
Revision as of 09:20, 1 April 2020
Mycobacterium tuberculosis alanine racemase inhibited by DCS
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