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| | <StructureSection load='5zqn' size='340' side='right'caption='[[5zqn]], [[Resolution|resolution]] 1.80Å' scene=''> | | <StructureSection load='5zqn' size='340' side='right'caption='[[5zqn]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5zqn]] is a 1 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=5ZQN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZQN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5zqn]] is a 1 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=5ZQN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZQN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IYP:(2R,3S)-2,3-DIHYDROXY-3-(1H-IMIDAZOL-5-YL)PROPYL+DIHYDROGEN+PHOSPHATE'>IYP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</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]] 1.8Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=IYP:(2R,3S)-2,3-DIHYDROXY-3-(1H-IMIDAZOL-5-YL)PROPYL+DIHYDROGEN+PHOSPHATE'>IYP</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">hisB, Rv1601, MTCY336.03c ([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/Imidazoleglycerol-phosphate_dehydratase Imidazoleglycerol-phosphate dehydratase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.19 4.2.1.19] </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=5zqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zqn OCA], [https://pdbe.org/5zqn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zqn RCSB], [https://www.ebi.ac.uk/pdbsum/5zqn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zqn 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=5zqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zqn OCA], [https://pdbe.org/5zqn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zqn RCSB], [https://www.ebi.ac.uk/pdbsum/5zqn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zqn ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/HIS7_MYCTU HIS7_MYCTU] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Imidazoleglycerol-phosphate dehydratase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Myctu]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Biswal, B K]] | + | [[Category: Biswal BK]] |
| - | [[Category: Kumar, D]] | + | [[Category: Kumar D]] |
| - | [[Category: Pal, R K]] | + | [[Category: Pal RK]] |
| - | [[Category: Hisb]]
| + | |
| - | [[Category: Lyase]]
| + | |
| - | [[Category: Modified cysteine]]
| + | |
| Structural highlights
Function
HIS7_MYCTU
Publication Abstract from PubMed
Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), employs ten enzymes including imidazoleglycerol-phosphate dehydratase (IGPD) for de novo biosynthesis of histidine. The absence of histidine-biosynthesis in humans combined with its essentiality for Mtb makes the enzymes of this pathway major anti-TB drug targets. We explored the inhibitory potential of a small molecule beta-(1,2,4-Triazole-3-yl)-DL-alanine (DLA) against Mtb IGPD. DLA exhibits an in vitro inhibitory efficacy in the lower micromolar range. Higher-resolution crystal structures of native and substrate-bound Mtb IGPD provided additional structural features of this important drug target. Crystal structure of IGPD-DLA complex at a resolution of 1.75 A, confirmed that DLA locks down the function of the enzyme by binding in the active site pocket of the IGPD mimicking the substrate-binding mode to a high degree. In our biochemical study, DLA showed an efficient inhibition of Mtb IGPD. Furthermore, DLA also showed bactericidal activity against Mtb and Mycobacterium smegmatis and inhibited their growth in respective culture medium. Importantly, owing to the favorable ADME and physicochemical properties, it serves as an important lead molecule for further derivatizations.
Characterization of a triazole scaffold compound as an inhibitor of Mycobacterium tuberculosis imidazoleglycerol-phosphate dehydratase.,Kumar D, Jha B, Bhatia I, Ashraf A, Dwivedy A, Biswal BK Proteins. 2021 Jul 20. doi: 10.1002/prot.26181. PMID:34288118[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kumar D, Jha B, Bhatia I, Ashraf A, Dwivedy A, Biswal BK. Characterization of a triazole scaffold compound as an inhibitor of Mycobacterium tuberculosis imidazoleglycerol-phosphate dehydratase. Proteins. 2021 Jul 20. doi: 10.1002/prot.26181. PMID:34288118 doi:http://dx.doi.org/10.1002/prot.26181
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