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| | ==Structure of Mycobacterium tuberculosis tryptophan synthase in space group F222== | | ==Structure of Mycobacterium tuberculosis tryptophan synthase in space group F222== |
| - | <StructureSection load='5ocw' size='340' side='right' caption='[[5ocw]], [[Resolution|resolution]] 4.00Å' scene=''> | + | <StructureSection load='5ocw' size='340' side='right'caption='[[5ocw]], [[Resolution|resolution]] 4.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ocw]] is a 24 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OCW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OCW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ocw]] is a 24 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OCW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OCW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=P1T:2-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]ACRYLIC+ACID'>P1T</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]] 4Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">trpA, Rv1613, MTCY01B2.05 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU]), trpB, Rv1612, MTCY01B2.04 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=P1T:2-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]ACRYLIC+ACID'>P1T</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Tryptophan_synthase Tryptophan synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.20 4.2.1.20] </span></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=5ocw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ocw OCA], [https://pdbe.org/5ocw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ocw RCSB], [https://www.ebi.ac.uk/pdbsum/5ocw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ocw ProSAT]</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=5ocw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ocw OCA], [http://pdbe.org/5ocw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ocw RCSB], [http://www.ebi.ac.uk/pdbsum/5ocw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ocw ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TRPA_MYCTU TRPA_MYCTU]] The alpha subunit is responsible for the aldol cleavage of indoleglycerol phosphate to indole and glyceraldehyde 3-phosphate. [[http://www.uniprot.org/uniprot/TRPB_MYCTU TRPB_MYCTU]] The beta subunit is responsible for the synthesis of L-tryptophan from indole and L-serine (By similarity). | + | [https://www.uniprot.org/uniprot/TRPA_MYCTU TRPA_MYCTU] The alpha subunit is responsible for the aldol cleavage of indoleglycerol phosphate to indole and glyceraldehyde 3-phosphate. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Tryptophan synthase|Tryptophan synthase]] | + | *[[Tryptophan synthase 3D structures|Tryptophan synthase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Myctu]] | + | [[Category: Large Structures]] |
| - | [[Category: Tryptophan synthase]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Abrahams, K]] | + | [[Category: Abrahams K]] |
| - | [[Category: Besra, G S]] | + | [[Category: Besra GS]] |
| - | [[Category: Cox, J A.G]] | + | [[Category: Cox JAG]] |
| - | [[Category: Futterer, K]] | + | [[Category: Futterer K]] |
| - | [[Category: Electron transport]]
| + | |
| - | [[Category: Tryptophan synthesis mycobacterium tuberculosis]]
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| Structural highlights
Function
TRPA_MYCTU The alpha subunit is responsible for the aldol cleavage of indoleglycerol phosphate to indole and glyceraldehyde 3-phosphate.
Publication Abstract from PubMed
Drug discovery efforts against the pathogen Mycobacterium tuberculosis (Mtb) have been advanced through phenotypic screens of extensive compound libraries. Such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 and 3 as potent inhibitors of mycobacterial growth. Optimization in the sulfolane series led to compound 4, which has proven activity in an in vivo murine model of Mtb infection. Here we identify the target and mode of inhibition of these compounds based on whole genome sequencing of spontaneous resistant mutants, which identified mutations locating to the essential alpha- and beta-subunits of tryptophan synthase. Over-expression studies confirmed tryptophan synthase as the biological target. Biochemical techniques probed the mechanism of inhibition, revealing the mutant enzyme complex incurs a fitness cost but does not prevent inhibitor binding. Mapping of the resistance conferring mutations onto a low-resolution crystal structure of Mtb tryptophan synthase showed they locate to the interface between the alpha- and beta-subunits. The discovery of anti-tubercular agents inhibiting tryptophan synthase highlights the therapeutic potential of this enzyme and draws attention to the prospect of other amino acid biosynthetic pathways as future Mtb drug targets.
Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface.,Abrahams KA, Cox JAG, Futterer K, Rullas J, Ortega-Muro F, Loman NJ, Moynihan PJ, Perez-Herran E, Jimenez E, Esquivias J, Barros D, Ballell L, Alemparte C, Besra GS Sci Rep. 2017 Aug 25;7(1):9430. doi: 10.1038/s41598-017-09642-y. PMID:28842600[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Abrahams KA, Cox JAG, Futterer K, Rullas J, Ortega-Muro F, Loman NJ, Moynihan PJ, Perez-Herran E, Jimenez E, Esquivias J, Barros D, Ballell L, Alemparte C, Besra GS. Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface. Sci Rep. 2017 Aug 25;7(1):9430. doi: 10.1038/s41598-017-09642-y. PMID:28842600 doi:http://dx.doi.org/10.1038/s41598-017-09642-y
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