5ibi

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<StructureSection load='5ibi' size='340' side='right'caption='[[5ibi]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
<StructureSection load='5ibi' size='340' side='right'caption='[[5ibi]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5ibi]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IBI OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5IBI FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5ibi]] 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=5IBI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IBI FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=69U:4,4-(5-{[(4-HYDROXYPHENYL)METHYL]AMINO}-1H-PYRAZOLE-3,4-DIYL)DIPHENOL'>69U</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">cyp121, cyp121_1, EI32_2700, ERS007657_00455, ERS007661_00083, ERS007663_02869, ERS007665_01035, ERS007670_00377, ERS007672_00334, ERS007679_00173, ERS007681_01277, ERS007703_02339, ERS007720_01219, ERS007722_01069, ERS013447_00077, ERS013471_02812, ERS023446_00317, ERS024276_01833, ERS027644_00398, ERS027652_00994, ERS027654_01464, ERS027656_01022, ERS027659_00311, ERS027666_00100, ERS031537_01827, ERS075357_02976, ERS075361_02508, ERS075387_01689, ERS124361_02646, HX90_2763 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=69U:4,4-(5-{[(4-HYDROXYPHENYL)METHYL]AMINO}-1H-PYRAZOLE-3,4-DIYL)DIPHENOL'>69U</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5ibi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ibi OCA], [http://pdbe.org/5ibi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ibi RCSB], [http://www.ebi.ac.uk/pdbsum/5ibi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ibi ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ibi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ibi OCA], [https://pdbe.org/5ibi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ibi RCSB], [https://www.ebi.ac.uk/pdbsum/5ibi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ibi ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/CP121_MYCTU CP121_MYCTU]
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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.
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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>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5ibi" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
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== References ==
 
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<references/>
 
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Levy, C]]
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[[Category: Mycobacterium tuberculosis]]
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[[Category: Mycobacterium tuberculosis cyp121 fragment based inhibitor screening]]
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[[Category: Levy C]]
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[[Category: Oxidoreductase]]
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Current revision

Crystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 26a

PDB ID 5ibi

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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