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| | <StructureSection load='5tcf' size='340' side='right'caption='[[5tcf]], [[Resolution|resolution]] 2.46Å' scene=''> | | <StructureSection load='5tcf' size='340' side='right'caption='[[5tcf]], [[Resolution|resolution]] 2.46Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tcf]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TCF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TCF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tcf]] is a 8 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=5TCF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TCF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</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]] 2.46Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[5tcg|5tcg]], [[5tch|5tch]], [[5tci|5tci]], [[5tcj|5tcj]]</div></td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">trpA, Rv1613, MTCY01B2.05 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU]), trpB, Rv1612, MTCY01B2.04 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Tryptophan_synthase Tryptophan synthase], with EC number [https://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=5tcf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tcf OCA], [https://pdbe.org/5tcf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tcf RCSB], [https://www.ebi.ac.uk/pdbsum/5tcf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tcf ProSAT]</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=5tcf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tcf OCA], [https://pdbe.org/5tcf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tcf RCSB], [https://www.ebi.ac.uk/pdbsum/5tcf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tcf ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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. [[https://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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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Myctu]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Tryptophan synthase]]
| + | [[Category: Jedrzejczak R]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Joachimiak A]] |
| - | [[Category: Jedrzejczak, R]] | + | [[Category: Maltseva N]] |
| - | [[Category: Joachimiak, A]] | + | [[Category: Michalska K]] |
| - | [[Category: Maltseva, N]] | + | |
| - | [[Category: Michalska, K]] | + | |
| - | [[Category: Allostery]]
| + | |
| - | [[Category: Amino acid biosynthesis]]
| + | |
| - | [[Category: Csgid]]
| + | |
| - | [[Category: Heterotetramer]]
| + | |
| - | [[Category: Lyase]]
| + | |
| - | [[Category: Plp]]
| + | |
| - | [[Category: Substrate channeling]]
| + | |
| 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
New antibiotics with novel targets are greatly needed. Bacteria have numerous essential functions, but only a small fraction of such processes-primarily those involved in macromolecular synthesis-are inhibited by current drugs. Targeting metabolic enzymes has been the focus of recent interest, but effective inhibitors have been difficult to identify. We describe a synthetic azetidine derivative, BRD4592, that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB), a previously untargeted, highly allosterically regulated enzyme. BRD4592 binds at the TrpAB alpha-beta-subunit interface and affects multiple steps in the enzyme's overall reaction, resulting in inhibition not easily overcome by changes in metabolic environment. We show that TrpAB is required for the survival of Mtb and Mycobacterium marinum in vivo and that this requirement may be independent of an adaptive immune response. This work highlights the effectiveness of allosteric inhibition for targeting proteins that are naturally highly dynamic and that are essential in vivo, despite their apparent dispensability under in vitro conditions, and suggests a framework for the discovery of a next generation of allosteric inhibitors.
A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase.,Wellington S, Nag PP, Michalska K, Johnston SE, Jedrzejczak RP, Kaushik VK, Clatworthy AE, Siddiqi N, McCarren P, Bajrami B, Maltseva NI, Combs S, Fisher SL, Joachimiak A, Schreiber SL, Hung DT Nat Chem Biol. 2017 Sep;13(9):943-950. doi: 10.1038/nchembio.2420. Epub 2017 Jul , 3. PMID:28671682[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wellington S, Nag PP, Michalska K, Johnston SE, Jedrzejczak RP, Kaushik VK, Clatworthy AE, Siddiqi N, McCarren P, Bajrami B, Maltseva NI, Combs S, Fisher SL, Joachimiak A, Schreiber SL, Hung DT. A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase. Nat Chem Biol. 2017 Sep;13(9):943-950. doi: 10.1038/nchembio.2420. Epub 2017 Jul , 3. PMID:28671682 doi:http://dx.doi.org/10.1038/nchembio.2420
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