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| - | [[Image:2a7s.gif|left|200px]] | |
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| - | {{Structure
| + | ==Crystal Structure of the Acyl-CoA Carboxylase, AccD5, from Mycobacterium tuberculosis== |
| - | |PDB= 2a7s |SIZE=350|CAPTION= <scene name='initialview01'>2a7s</scene>, resolution 2.90Å
| + | <StructureSection load='2a7s' size='340' side='right'caption='[[2a7s]], [[Resolution|resolution]] 2.90Å' scene=''> |
| - | |SITE=
| + | == Structural highlights == |
| - | |LIGAND=
| + | <table><tr><td colspan='2'>[[2a7s]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A7S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2A7S FirstGlance]. <br> |
| - | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Propionyl-CoA_carboxylase Propionyl-CoA carboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.4.1.3 6.4.1.3] </span>
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</td></tr> |
| - | |GENE= accD5, pccB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis])
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2a7s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a7s OCA], [https://pdbe.org/2a7s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2a7s RCSB], [https://www.ebi.ac.uk/pdbsum/2a7s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2a7s ProSAT]</span></td></tr> |
| - | |DOMAIN=
| + | </table> |
| - | |RELATEDENTRY=
| + | == Function == |
| - | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2a7s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a7s OCA], [http://www.ebi.ac.uk/pdbsum/2a7s PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2a7s RCSB]</span>
| + | [https://www.uniprot.org/uniprot/ACCD5_MYCTU ACCD5_MYCTU] Component of a biotin-dependent acyl-CoA carboxylase complex. This subunit transfers the CO2 from carboxybiotin to the CoA ester substrate (PubMed:16354663, PubMed:16385038, PubMed:28222482). When associated with the alpha3 subunit AccA3, is involved in the carboxylation of acetyl-CoA and propionyl-CoA, with a preference for propionyl-CoA (PubMed:16354663, PubMed:16385038, PubMed:28222482). Is also required for the activity of the long-chain acyl-CoA carboxylase (LCC) complex (PubMed:28222482).<ref>PMID:16354663</ref> <ref>PMID:16385038</ref> <ref>PMID:28222482</ref> |
| - | }}
| + | == Evolutionary Conservation == |
| - | | + | [[Image:Consurf_key_small.gif|200px|right]] |
| - | '''Crystal Structure of the Acyl-CoA Carboxylase, AccD5, from Mycobacterium tuberculosis'''
| + | Check<jmol> |
| - | | + | <jmolCheckbox> |
| - | | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a7/2a7s_consurf.spt"</scriptWhenChecked> |
| - | ==Overview== | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| - | Mycolic acids and multimethyl-branched fatty acids are found uniquely in the cell envelope of pathogenic mycobacteria. These unusually long fatty acids are essential for the survival, virulence, and antibiotic resistance of Mycobacterium tuberculosis. Acyl-CoA carboxylases (ACCases) commit acyl-CoAs to the biosynthesis of these unique fatty acids. Unlike other organisms such as Escherichia coli or humans that have only one or two ACCases, M. tuberculosis contains six ACCase carboxyltransferase domains, AccD1-6, whose specific roles in the pathogen are not well defined. Previous studies indicate that AccD4, AccD5, and AccD6 are important for cell envelope lipid biosynthesis and that its disruption leads to pathogen death. We have determined the 2.9-Angstroms crystal structure of AccD5, whose sequence, structure, and active site are highly conserved with respect to the carboxyltransferase domain of the Streptomyces coelicolor propionyl-CoA carboxylase. Contrary to the previous proposal that AccD4-5 accept long-chain acyl-CoAs as their substrates, both crystal structure and kinetic assay indicate that AccD5 prefers propionyl-CoA as its substrate and produces methylmalonyl-CoA, the substrate for the biosyntheses of multimethyl-branched fatty acids such as mycocerosic, phthioceranic, hydroxyphthioceranic, mycosanoic, and mycolipenic acids. Extensive in silico screening of National Cancer Institute compounds and the University of California, Irvine, ChemDB database resulted in the identification of one inhibitor with a K(i) of 13.1 microM. Our results pave the way toward understanding the biological roles of key ACCases that commit acyl-CoAs to the biosynthesis of cell envelope fatty acids, in addition to providing a target for structure-based development of antituberculosis therapeutics.
| + | <text>to colour the structure by Evolutionary Conservation</text> |
| - | | + | </jmolCheckbox> |
| - | ==About this Structure== | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2a7s ConSurf]. |
| - | 2A7S is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A7S OCA].
| + | <div style="clear:both"></div> |
| - | | + | == References == |
| - | ==Reference== | + | <references/> |
| - | Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis., Lin TW, Melgar MM, Kurth D, Swamidass SJ, Purdon J, Tseng T, Gago G, Baldi P, Gramajo H, Tsai SC, Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3072-7. Epub 2006 Feb 21. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16492739 16492739]
| + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Large Structures]] |
| | [[Category: Mycobacterium tuberculosis]] | | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Propionyl-CoA carboxylase]]
| + | [[Category: Lin T]] |
| - | [[Category: Single protein]]
| + | [[Category: Melgar M]] |
| - | [[Category: Lin, T.]] | + | [[Category: Purdon J]] |
| - | [[Category: Melgar, M.]] | + | [[Category: Tsai SC]] |
| - | [[Category: Purdon, J.]] | + | [[Category: Tseng T]] |
| - | [[Category: Tsai, S C.]] | + | |
| - | [[Category: Tseng, T.]] | + | |
| - | [[Category: acetyl-coa carboxylase]]
| + | |
| - | [[Category: acyl-coa carboxylase]]
| + | |
| - | [[Category: carboxylase]]
| + | |
| - | [[Category: carboxyltransferase]]
| + | |
| - | [[Category: fatty acid]]
| + | |
| - | [[Category: mycolic acid]]
| + | |
| - | [[Category: polyketide]]
| + | |
| - | [[Category: propionyl-coa carboxylase]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:48:59 2008''
| + | |
