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| ==Crystal structure of S-adenosylmethionine synthetase from Mycobacterium marinum== | | ==Crystal structure of S-adenosylmethionine synthetase from Mycobacterium marinum== |
| <StructureSection load='3rv2' size='340' side='right' caption='[[3rv2]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='3rv2' size='340' side='right'caption='[[3rv2]], [[Resolution|resolution]] 2.00Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[3rv2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycmm Mycmm]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RV2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RV2 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[3rv2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_marinum_M Mycobacterium marinum M]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RV2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RV2 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3iml|3iml]]</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">metK, MMAR_2205 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=216594 MYCMM])</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=3rv2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rv2 OCA], [https://pdbe.org/3rv2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rv2 RCSB], [https://www.ebi.ac.uk/pdbsum/3rv2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rv2 ProSAT]</span></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Methionine_adenosyltransferase Methionine adenosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.6 2.5.1.6] </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=3rv2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rv2 OCA], [http://pdbe.org/3rv2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3rv2 RCSB], [http://www.ebi.ac.uk/pdbsum/3rv2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3rv2 ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/METK_MYCMM METK_MYCMM]] Catalyzes the formation of S-adenosylmethionine from methionine and ATP. The overall synthetic reaction is composed of two sequential steps, AdoMet formation and the subsequent tripolyphosphate hydrolysis which occurs prior to release of AdoMet from the enzyme.[HAMAP-Rule:MF_00086] | | [https://www.uniprot.org/uniprot/METK_MYCMM METK_MYCMM] Catalyzes the formation of S-adenosylmethionine from methionine and ATP. The overall synthetic reaction is composed of two sequential steps, AdoMet formation and the subsequent tripolyphosphate hydrolysis which occurs prior to release of AdoMet from the enzyme.[HAMAP-Rule:MF_00086] |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Calpha RMSD <1 A, >85% side chain identity, and >/=80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.
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| Increasing the structural coverage of tuberculosis drug targets.,Baugh L, Phan I, Begley DW, Clifton MC, Armour B, Dranow DM, Taylor BM, Muruthi MM, Abendroth J, Fairman JW, Fox D 3rd, Dieterich SH, Staker BL, Gardberg AS, Choi R, Hewitt SN, Napuli AJ, Myers J, Barrett LK, Zhang Y, Ferrell M, Mundt E, Thompkins K, Tran N, Lyons-Abbott S, Abramov A, Sekar A, Serbzhinskiy D, Lorimer D, Buchko GW, Stacy R, Stewart LJ, Edwards TE, Van Voorhis WC, Myler PJ Tuberculosis (Edinb). 2014 Dec 19. pii: S1472-9792(14)20565-8. doi:, 10.1016/j.tube.2014.12.003. PMID:25613812<ref>PMID:25613812</ref>
| | ==See Also== |
| | | *[[S-adenosylmethionine synthetase 3D structures|S-adenosylmethionine synthetase 3D structures]] |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 3rv2" style="background-color:#fffaf0;"></div>
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| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Methionine adenosyltransferase]] | | [[Category: Large Structures]] |
| [[Category: Mycmm]] | | [[Category: Mycobacterium marinum M]] |
| [[Category: Structural genomic]]
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| [[Category: Adomet]]
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| [[Category: Adomet synthase]]
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| [[Category: Methyl donor]]
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| [[Category: Methylation]]
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| [[Category: S-adenosylmethionine]]
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| [[Category: Sam]]
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| [[Category: Ssgcid]]
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| [[Category: Transferase]]
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