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5ibe

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==Crystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 25a==
==Crystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 25a==
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<StructureSection load='5ibe' size='340' side='right' caption='[[5ibe]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
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<StructureSection load='5ibe' size='340' side='right'caption='[[5ibe]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5ibe]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IBE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IBE FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5ibe]] 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=5IBE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IBE FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=69M:4-[5-AMINO-4-(3-AMINO[1,1-BIPHENYL]-3-YL)-1H-PYRAZOL-3-YL]PHENOL'>69M</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</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]] 1.624&#8491;</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mycocyclosin_synthase Mycocyclosin synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.21.9 1.14.21.9] </span></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=69M:4-[5-AMINO-4-(3-AMINO[1,1-BIPHENYL]-3-YL)-1H-PYRAZOL-3-YL]PHENOL'>69M</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ibe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ibe OCA], [http://pdbe.org/5ibe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ibe RCSB], [http://www.ebi.ac.uk/pdbsum/5ibe PDBsum]</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=5ibe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ibe OCA], [https://pdbe.org/5ibe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ibe RCSB], [https://www.ebi.ac.uk/pdbsum/5ibe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ibe ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/CP121_MYCTO CP121_MYCTO]] Catalyzes C-C bond formation between the carbons ortho to the phenolic hydroxyl of cyclo(L-tyr-L-tyr) (cYY) producing mycocyclosin. Can also use cyclo(L-Tyr-L-Phe) (cYF), cyclo(L-Tyr-L-Trp) (cYW) and cyclo(L-Tyr-L-3,4-dihydroxyphenylalanine) (cY-DOPA) as substrate (By similarity).
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[https://www.uniprot.org/uniprot/CP121_MYCTU CP121_MYCTU]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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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==See Also==
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*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
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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 5ibe" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Mycocyclosin synthase]]
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[[Category: Large Structures]]
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[[Category: Levy, C]]
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[[Category: Cyp121]]
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[[Category: Fragment based inhibitor screening]]
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[[Category: Mycobacterium tuberculosis]]
[[Category: Mycobacterium tuberculosis]]
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[[Category: Oxidoreductase]]
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[[Category: Levy C]]

Current revision

Crystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 25a

PDB ID 5ibe

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