5ibd

From Proteopedia

(Difference between revisions)

Revision as of 07:11, 3 June 2020

Crystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 24a

Structural highlights

5ibd is a 1 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	cyp121, MT2336 ("Bacillus tuberculosis" (Zopf 1883) Klein 1884)
Activity:	Mycocyclosin synthase, with EC number 1.14.21.9
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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).

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.

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5ibd"

@@ Line 1: / Line 1: @@
 ==Crystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 24a==
-<StructureSection load='5ibd' size='340' side='right' caption='[[5ibd]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
+<StructureSection load='5ibd' size='340' side='right'caption='[[5ibd]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ibd]] is a 1 chain structure. 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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IBD FirstGlance]. <br>
+<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>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='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='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='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'>[http://oca.weizmann.ac.il/oca-docs/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]</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>
 == Function ==
@@ Line 19: / Line 20: @@
 </div>
 <div class="pdbe-citations 5ibd" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Mycocyclosin synthase]]
 [[Category: Levy, C]]

5ibd

From Proteopedia

Revision as of 07:11, 3 June 2020

Crystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 24a

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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