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| | <StructureSection load='5ibd' size='340' side='right'caption='[[5ibd]], [[Resolution|resolution]] 1.77Å' scene=''> | | <StructureSection load='5ibd' size='340' side='right'caption='[[5ibd]], [[Resolution|resolution]] 1.77Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ibd]] 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=5IBD OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5IBD FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ibd]] 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=5IBD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IBD FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GGJ:4-(3-AMINO[1,1-BIPHENYL]-3-YL)-3-(4-METHOXYPHENYL)-1H-PYRAZOL-5-AMINE'>GGJ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.77Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">cyp121, MT2336 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GGJ:4-(3-AMINO[1,1-BIPHENYL]-3-YL)-3-(4-METHOXYPHENYL)-1H-PYRAZOL-5-AMINE'>GGJ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <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>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ibd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ibd OCA], [https://pdbe.org/5ibd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ibd RCSB], [https://www.ebi.ac.uk/pdbsum/5ibd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ibd ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5ibd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ibd OCA], [http://pdbe.org/5ibd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ibd RCSB], [http://www.ebi.ac.uk/pdbsum/5ibd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ibd ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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). | + | [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: Mycocyclosin synthase]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Levy, C]] | + | [[Category: Levy C]] |
| - | [[Category: Fragment based inhibitor screening]]
| + | |
| - | [[Category: Mycobacterium tuberculosis cyp121]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Function
CP121_MYCTU
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors. J Med Chem. 2016 Apr 14;59(7):3272-302. doi: 10.1021/acs.jmedchem.6b00007. Epub, 2016 Mar 22. PMID:27002486 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00007
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