5tci: Difference between revisions
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==Crystal structure of tryptophan synthase from M. tuberculosis - BRD4592-bound form== | ==Crystal structure of tryptophan synthase from M. tuberculosis - BRD4592-bound form== | ||
<StructureSection load='5tci' size='340' side='right' caption='[[5tci]], [[Resolution|resolution]] 2.45Å' scene=''> | <StructureSection load='5tci' size='340' side='right'caption='[[5tci]], [[Resolution|resolution]] 2.45Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5tci]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TCI OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5tci]] 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=5TCI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TCI FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=79V:(2R,3S,4R)-3-(2-fluoro[1,1-biphenyl]-4-yl)-4-(hydroxymethyl)azetidine-2-carbonitrile'>79V</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.45Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=79V:(2R,3S,4R)-3-(2-fluoro[1,1-biphenyl]-4-yl)-4-(hydroxymethyl)azetidine-2-carbonitrile'>79V</scene>, <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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5tci FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tci OCA], [https://pdbe.org/5tci PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tci RCSB], [https://www.ebi.ac.uk/pdbsum/5tci PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tci ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5tci" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5tci" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Tryptophan synthase 3D structures|Tryptophan synthase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
[[Category: Fisher | [[Category: Fisher SL]] | ||
[[Category: Hung | [[Category: Hung DT]] | ||
[[Category: Jedrzejczak | [[Category: Jedrzejczak R]] | ||
[[Category: Joachimiak | [[Category: Joachimiak A]] | ||
[[Category: Maltseva | [[Category: Maltseva N]] | ||
[[Category: Michalska | [[Category: Michalska K]] | ||
[[Category: Nag | [[Category: Nag PP]] | ||
[[Category: Schreiber | [[Category: Schreiber SL]] | ||
[[Category: Wellington | [[Category: Wellington S]] | ||
Latest revision as of 15:57, 4 October 2023
Crystal structure of tryptophan synthase from M. tuberculosis - BRD4592-bound formCrystal structure of tryptophan synthase from M. tuberculosis - BRD4592-bound form
Structural highlights
FunctionTRPA_MYCTU The alpha subunit is responsible for the aldol cleavage of indoleglycerol phosphate to indole and glyceraldehyde 3-phosphate. Publication Abstract from PubMedNew 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 AlsoReferences
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