6geo: Difference between revisions
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<StructureSection load='6geo' size='340' side='right'caption='[[6geo]], [[Resolution|resolution]] 1.50Å' scene=''> | <StructureSection load='6geo' size='340' side='right'caption='[[6geo]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6geo]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GEO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GEO FirstGlance]. <br> | <table><tr><td colspan='2'>[[6geo]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycto Mycto]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GEO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GEO FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EW2:2-chloranyl-3-[4-(imidazol-1-ylmethyl)-1-phenyl-pyrazol-3-yl]-1~{H}-indole'>EW2</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"><scene name='pdbligand=EW2:2-chloranyl-3-[4-(imidazol-1-ylmethyl)-1-phenyl-pyrazol-3-yl]-1~{H}-indole'>EW2</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=83331 MYCTO])</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='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=6geo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6geo OCA], [http://pdbe.org/6geo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6geo RCSB], [http://www.ebi.ac.uk/pdbsum/6geo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6geo ProSAT]</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=6geo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6geo OCA], [http://pdbe.org/6geo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6geo RCSB], [http://www.ebi.ac.uk/pdbsum/6geo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6geo ProSAT]</span></td></tr> | ||
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== 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). | [[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). | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The emergence of untreatable drug-resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (K D). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert-butyl (10 g) compounds displaying optimal activity (MIC 1.562 mug/mL, K D 0.22 muM (10 f) and 4.81 muM (10 g)). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H-bond acceptors/H-bond donors 4/0, number of rotatable bonds 5-6, molecular volume >340 A(3), topological polar surface area <40 A(2). | |||
Design and Synthesis of Imidazole and Triazole Pyrazoles as Mycobacterium Tuberculosis CYP121A1 Inhibitors.,Kishk SM, McLean KJ, Sood S, Smith D, Evans JWD, Helal MA, Gomaa MS, Salama I, Mostafa SM, de Carvalho LPS, Levy CW, Munro AW, Simons C ChemistryOpen. 2019 Jul 23;8(7):995-1011. doi: 10.1002/open.201900227., eCollection 2019 Jul. PMID:31367508<ref>PMID:31367508</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6geo" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Mycocyclosin synthase]] | [[Category: Mycocyclosin synthase]] | ||
[[Category: Mycto]] | |||
[[Category: Levy, C W]] | [[Category: Levy, C W]] | ||
[[Category: Antibiotic]] | [[Category: Antibiotic]] | ||
[[Category: Inhibitor complex p450]] | [[Category: Inhibitor complex p450]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
Latest revision as of 20:19, 14 August 2019
Crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP121A1 in complex with Triazole Pyrazole inhibitor 10jCrystal structure of Mycobacterium tuberculosis cytochrome P450 CYP121A1 in complex with Triazole Pyrazole inhibitor 10j
Structural highlights
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 PubMedThe emergence of untreatable drug-resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (K D). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert-butyl (10 g) compounds displaying optimal activity (MIC 1.562 mug/mL, K D 0.22 muM (10 f) and 4.81 muM (10 g)). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H-bond acceptors/H-bond donors 4/0, number of rotatable bonds 5-6, molecular volume >340 A(3), topological polar surface area <40 A(2). Design and Synthesis of Imidazole and Triazole Pyrazoles as Mycobacterium Tuberculosis CYP121A1 Inhibitors.,Kishk SM, McLean KJ, Sood S, Smith D, Evans JWD, Helal MA, Gomaa MS, Salama I, Mostafa SM, de Carvalho LPS, Levy CW, Munro AW, Simons C ChemistryOpen. 2019 Jul 23;8(7):995-1011. doi: 10.1002/open.201900227., eCollection 2019 Jul. PMID:31367508[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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