3r9c: Difference between revisions
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==Crystal structure of Mycobacterium smegmatis CYP164A2 with Econazole bound== | ==Crystal structure of Mycobacterium smegmatis CYP164A2 with Econazole bound== | ||
<StructureSection load='3r9c' size='340' side='right' caption='[[3r9c]], [[Resolution|resolution]] 2.14Å' scene=''> | <StructureSection load='3r9c' size='340' side='right'caption='[[3r9c]], [[Resolution|resolution]] 2.14Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3r9c]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3r9c]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycs2 Mycs2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3R9C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3R9C FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ECL:1-[(2R)-2-[(4-CHLOROBENZYL)OXY]-2-(2,4-DICHLOROPHENYL)ETHYL]-1H-IMIDAZOLE'>ECL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ECL:1-[(2R)-2-[(4-CHLOROBENZYL)OXY]-2-(2,4-DICHLOROPHENYL)ETHYL]-1H-IMIDAZOLE'>ECL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3r9b|3r9b]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3r9b|3r9b]]</div></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3r9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3r9c OCA], [https://pdbe.org/3r9c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3r9c RCSB], [https://www.ebi.ac.uk/pdbsum/3r9c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3r9c ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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==See Also== | ==See Also== | ||
*[[Cytochrome P450|Cytochrome P450]] | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Mycs2]] | [[Category: Mycs2]] | ||
[[Category: Agnew, C R.J]] | [[Category: Agnew, C R.J]] | ||
Revision as of 08:54, 15 June 2022
Crystal structure of Mycobacterium smegmatis CYP164A2 with Econazole boundCrystal structure of Mycobacterium smegmatis CYP164A2 with Econazole bound
Structural highlights
Publication Abstract from PubMedCYP164 family P450 enzymes are found in only a subset of mycobacteria and include CYP164A1, which is the sole P450 found in Mycobacterium leprae, the causative agent of leprosy. This has previously led to interest in this enzyme as a potential drug target. Here we describe the first crystal structure of a CYP164 enzyme, CYP164A2 from Mycobacterium smegmatis. CYP164A2 has a distinctive, enlarged hydrophobic active site that extends above the porphyrin ring toward the access channels. Unusually, we find that CYP164A2 can simultaneously bind two econazole molecules in different regions of the enlarged active site and is accompanied by the rearrangement and ordering of the BC loop. The primary location is through a classic interaction of the azole group with the porphyrin iron. The second econazole molecule is bound to a unique site and is linked to a tetracoordinated metal ion complexed to one of the heme carboxylates and to the side chains of His 105 and His 364. All of these features are preserved in the closely homologous M. leprae CYP164A1. The computational docking of azole compounds to a homology model of CYP164A1 suggests that these compounds will form effective inhibitors and is supported by the correlation of parallel docking with experimental binding studies of CYP164A2. The binding of econazole to CYP164A2 occurs primarily through the high-spin "open" conformation of the enzyme (K(d) [dissociation constant] of 0.1 muM), with binding to the low-spin "closed" form being significantly hindered (K(d) of 338 muM). These studies support previous suggestions that azole derivatives may provide an effective strategy to improve the treatment of leprosy. An enlarged, adaptable active site in CYP164 family P450 enzymes, the sole P450 in Mycobacterium leprae.,Agnew CR, Warrilow AG, Burton NM, Lamb DC, Kelly SL, Brady RL Antimicrob Agents Chemother. 2012 Jan;56(1):391-402. Epub 2011 Oct 28. PMID:22037849[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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