5ibh: Difference between revisions
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<StructureSection load='5ibh' size='340' side='right'caption='[[5ibh]], [[Resolution|resolution]] 2.02Å' scene=''> | <StructureSection load='5ibh' size='340' side='right'caption='[[5ibh]], [[Resolution|resolution]] 2.02Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5ibh]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5ibh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IBH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IBH FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=69R:4,4-(5-{[(1H-IMIDAZOL-4-YL)METHYL]AMINO}-1H-PYRAZOLE-3,4-DIYL)DIPHENOL'>69R</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.0201Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=69R:4,4-(5-{[(1H-IMIDAZOL-4-YL)METHYL]AMINO}-1H-PYRAZOLE-3,4-DIYL)DIPHENOL'>69R</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ibh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ibh OCA], [https://pdbe.org/5ibh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ibh RCSB], [https://www.ebi.ac.uk/pdbsum/5ibh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ibh ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/CP121_MYCTU CP121_MYCTU] | |||
<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: Mycobacterium tuberculosis]] | |||
[[Category: Mycobacterium tuberculosis | [[Category: Levy C]] | ||
[[Category: | |||
Revision as of 16:44, 30 August 2023
Crystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 26hCrystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 26h
Structural highlights
FunctionPublication Abstract from PubMedThe essential enzyme CYP121 is a target for drug development against antibiotic resistant strains of Mycobacterium tuberculosis. A triazol-1-yl phenol fragment 1 was identified to bind to CYP121 using a cascade of biophysical assays. Synthetic merging and optimization of 1 produced a 100-fold improvement in binding affinity, yielding lead compound 2 (KD = 15 muM). Deconstruction of 2 into its component retrofragments allowed the group efficiency of structural motifs to be assessed, the identification of more LE scaffolds for optimization and highlighted binding affinity hotspots. Structure-guided addition of a metal-binding pharmacophore onto LE retrofragment scaffolds produced low nanomolar (KD = 15 nM) CYP121 ligands. Elaboration of these compounds to target binding hotspots in the distal active site afforded compounds with excellent selectivity against human drug-metabolizing P450s. Analysis of the factors governing ligand potency and selectivity using X-ray crystallography, UV-vis spectroscopy, and native mass spectrometry provides insight for subsequent drug development. Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors.,Kavanagh ME, Coyne AG, McLean KJ, James GG, Levy CW, Marino LB, de Carvalho LP, Chan DS, Hudson SA, Surade S, Leys D, Munro AW, Abell C J Med Chem. 2016 Apr 14;59(7):3272-302. doi: 10.1021/acs.jmedchem.6b00007. Epub, 2016 Mar 22. PMID:27002486[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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