6u6c: Difference between revisions
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==== | ==Crystal structure of tryptophan synthase from M. tuberculosis - aminoacrylate- and GSK2-bound form== | ||
<StructureSection load='6u6c' size='340' side='right'caption='[[6u6c]]' scene=''> | <StructureSection load='6u6c' size='340' side='right'caption='[[6u6c]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6u6c]] 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=6U6C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U6C FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.402Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ALA:ALANINE'>ALA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=P1T:2-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]ACRYLIC+ACID'>P1T</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=PZV:1-(2-fluorobenzene-1-carbonyl)-N-methyl-2,3-dihydro-1H-indole-5-sulfonamide'>PZV</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=6u6c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u6c OCA], [https://pdbe.org/6u6c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u6c RCSB], [https://www.ebi.ac.uk/pdbsum/6u6c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u6c ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== 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;"> | |||
== Publication Abstract from PubMed == | |||
Global dispersion of multidrug resistant bacteria is very common and evolution of antibiotic-resistance is occurring at an alarming rate, presenting a formidable challenge for humanity. The development of new therapeuthics with novel molecular targets is urgently needed. Current drugs primarily affect protein, nucleic acid, and cell wall synthesis. Metabolic pathways, including those involved in amino acid biosynthesis, have recently sparked interest in the drug discovery community as potential reservoirs of such novel targets. Tryptophan biosynthesis, utilized by bacteria but absent in humans, represents one of the currently studied processes with a therapeutic focus. It has been shown that tryptophan synthase (TrpAB) is required for survival of Mycobacterium tuberculosis in macrophages and for evading host defense, and therefore is a promising drug target. Here we present crystal structures of TrpAB with two allosteric inhibitors of M. tuberculosis tryptophan synthase that belong to sulfolane and indole-5-sulfonamide chemical scaffolds. We compare our results with previously reported structural and biochemical studies of another, azetidine-containing M. tuberculosis tryptophan synthase inhibitor. This work shows how structurally distinct ligands can occupy the same allosteric site and make specific interactions. It also highlights the potential benefit of targeting more variable allosteric sites of important metabolic enzymes. | |||
Allosteric inhibitors of Mycobacterium tuberculosis tryptophan synthase.,Michalska K, Chang C, Maltseva NI, Jedrzejczak R, Robertson GT, Gusovsky F, McCarren P, Schreiber SL, Nag PP, Joachimiak A Protein Sci. 2020 Mar;29(3):779-788. doi: 10.1002/pro.3825. Epub 2020 Jan 20. PMID:31930594<ref>PMID:31930594</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6u6c" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Tryptophan synthase 3D structures|Tryptophan synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
[[Category: Chang C]] | |||
[[Category: Jedrzejczak R]] | |||
[[Category: Joachimiak A]] | |||
[[Category: Maltseva NI]] | |||
[[Category: McCarren P]] | |||
[[Category: Michalska K]] | |||
[[Category: Nag PP]] | |||
Latest revision as of 10:44, 11 October 2023
Crystal structure of tryptophan synthase from M. tuberculosis - aminoacrylate- and GSK2-bound formCrystal structure of tryptophan synthase from M. tuberculosis - aminoacrylate- and GSK2-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 PubMedGlobal dispersion of multidrug resistant bacteria is very common and evolution of antibiotic-resistance is occurring at an alarming rate, presenting a formidable challenge for humanity. The development of new therapeuthics with novel molecular targets is urgently needed. Current drugs primarily affect protein, nucleic acid, and cell wall synthesis. Metabolic pathways, including those involved in amino acid biosynthesis, have recently sparked interest in the drug discovery community as potential reservoirs of such novel targets. Tryptophan biosynthesis, utilized by bacteria but absent in humans, represents one of the currently studied processes with a therapeutic focus. It has been shown that tryptophan synthase (TrpAB) is required for survival of Mycobacterium tuberculosis in macrophages and for evading host defense, and therefore is a promising drug target. Here we present crystal structures of TrpAB with two allosteric inhibitors of M. tuberculosis tryptophan synthase that belong to sulfolane and indole-5-sulfonamide chemical scaffolds. We compare our results with previously reported structural and biochemical studies of another, azetidine-containing M. tuberculosis tryptophan synthase inhibitor. This work shows how structurally distinct ligands can occupy the same allosteric site and make specific interactions. It also highlights the potential benefit of targeting more variable allosteric sites of important metabolic enzymes. Allosteric inhibitors of Mycobacterium tuberculosis tryptophan synthase.,Michalska K, Chang C, Maltseva NI, Jedrzejczak R, Robertson GT, Gusovsky F, McCarren P, Schreiber SL, Nag PP, Joachimiak A Protein Sci. 2020 Mar;29(3):779-788. doi: 10.1002/pro.3825. Epub 2020 Jan 20. PMID:31930594[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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