|
|
| Line 3: |
Line 3: |
| | <StructureSection load='5tch' size='340' side='right'caption='[[5tch]], [[Resolution|resolution]] 2.35Å' scene=''> | | <StructureSection load='5tch' size='340' side='right'caption='[[5tch]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tch]] 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=5TCH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TCH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tch]] 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=5TCH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TCH 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=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]] 2.35Å</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=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;'>[[5tcf|5tcf]], [[5tcg|5tcg]], [[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=5tch FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tch OCA], [https://pdbe.org/5tch PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tch RCSB], [https://www.ebi.ac.uk/pdbsum/5tch PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tch 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=5tch FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tch OCA], [https://pdbe.org/5tch PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tch RCSB], [https://www.ebi.ac.uk/pdbsum/5tch PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tch 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;">
| + | |
| - | == 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<ref>PMID:28671682</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 5tch" style="background-color:#fffaf0;"></div>
| + | |
| | | | |
| | ==See Also== | | ==See Also== |
| | *[[Tryptophan synthase 3D structures|Tryptophan synthase 3D structures]] | | *[[Tryptophan synthase 3D structures|Tryptophan synthase 3D structures]] |
| - | == References == | |
| - | <references/> | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Myctu]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Tryptophan synthase]]
| + | [[Category: Fisher SL]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Hung DT]] |
| - | [[Category: Fisher, S L]] | + | [[Category: Jedrzejczak R]] |
| - | [[Category: Hung, D T]] | + | [[Category: Joachimiak A]] |
| - | [[Category: Jedrzejczak, R]] | + | [[Category: Maltseva N]] |
| - | [[Category: Joachimiak, A]] | + | [[Category: Michalska K]] |
| - | [[Category: Maltseva, N]] | + | [[Category: Nag PP]] |
| - | [[Category: Michalska, K]] | + | [[Category: Schreiber SL]] |
| - | [[Category: Nag, P P]] | + | [[Category: Wellington S]] |
| - | [[Category: Schreiber, S L]] | + | |
| - | [[Category: Wellington, S]] | + | |
| - | [[Category: Allostery]]
| + | |
| - | [[Category: Amino acid biosynthesis]]
| + | |
| - | [[Category: Csgid]]
| + | |
| - | [[Category: Heterotetramer]]
| + | |
| - | [[Category: Lyase]]
| + | |
| - | [[Category: Plp]]
| + | |
| - | [[Category: Substrate channeling]]
| + | |
