5edt: Difference between revisions
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The | ==Crystal structure of Mycobacterium tuberculosis CYP121 in complex with LIG9== | ||
<StructureSection load='5edt' size='340' side='right'caption='[[5edt]], [[Resolution|resolution]] 2.45Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5edt]] 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=5EDT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EDT FirstGlance]. <br> | |||
</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=5MK:2-AZANYL-5-CHLORANYL-BENZAMIDE'>5MK</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'>[https://proteopedia.org/fgij/fg.htm?mol=5edt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5edt OCA], [https://pdbe.org/5edt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5edt RCSB], [https://www.ebi.ac.uk/pdbsum/5edt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5edt ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CP121_MYCBO CP121_MYCBO] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The 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<ref>PMID:27002486</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5edt" style="background-color:#fffaf0;"></div> | ||
[[Category: Abell | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Marino | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
[[Category: | [[Category: Abell C]] | ||
[[Category: | [[Category: Carvalho LPD]] | ||
[[Category: Chan DSH]] | |||
[[Category: Coyne AG]] | |||
[[Category: Hudson SA]] | |||
[[Category: James GG]] | |||
[[Category: Kavanagh ME]] | |||
[[Category: Levy C]] | |||
[[Category: Marino LB]] | |||
[[Category: McLean KJ]] | |||
[[Category: Munro AW]] | |||
[[Category: Surade S]] | |||
Latest revision as of 09:22, 5 July 2023
Crystal structure of Mycobacterium tuberculosis CYP121 in complex with LIG9Crystal structure of Mycobacterium tuberculosis CYP121 in complex with LIG9
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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