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| | ==4,4'-Dihydroxybenzophenone Mimics Sterol Substrate in the Binding Site of Sterol 14alpha-Demethylase (CYP51) in the X-ray Structure of the Complex== | | ==4,4'-Dihydroxybenzophenone Mimics Sterol Substrate in the Binding Site of Sterol 14alpha-Demethylase (CYP51) in the X-ray Structure of the Complex== |
| - | <StructureSection load='2vku' size='340' side='right' caption='[[2vku]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='2vku' size='340' side='right'caption='[[2vku]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2vku]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VKU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2VKU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2vku]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VKU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VKU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DBE:BIS(4-HYDROXYPHENYL)METHANONE'>DBE</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]] 1.95Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ea1|1ea1]], [[1u13|1u13]], [[2bz9|2bz9]], [[2ci0|2ci0]], [[2cib|2cib]], [[1e9x|1e9x]], [[1h5z|1h5z]], [[1x8v|1x8v]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DBE:BIS(4-HYDROXYPHENYL)METHANONE'>DBE</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/Sterol_14-demethylase Sterol 14-demethylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.70 1.14.13.70] </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=2vku FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vku OCA], [https://pdbe.org/2vku PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vku RCSB], [https://www.ebi.ac.uk/pdbsum/2vku PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vku 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=2vku FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vku OCA], [http://pdbe.org/2vku PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2vku RCSB], [http://www.ebi.ac.uk/pdbsum/2vku PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2vku ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP51_MYCTU CP51_MYCTU]] Its precise biological substrate is not known. Catalyzes C14-demethylation of lanosterol, 24,25-dihydrolanosterol and obtusifoliol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.<ref>PMID:9756611</ref> <ref>PMID:10430874</ref> | + | [https://www.uniprot.org/uniprot/CP51_MYCTU CP51_MYCTU] Its precise biological substrate is not known. Catalyzes C14-demethylation of lanosterol, 24,25-dihydrolanosterol and obtusifoliol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.<ref>PMID:9756611</ref> <ref>PMID:10430874</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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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: Myctu]] | + | [[Category: Large Structures]] |
| - | [[Category: Sterol 14-demethylase]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Eddine, A N]] | + | [[Category: Eddine AN]] |
| - | [[Category: Kries, J P.von]]
| + | [[Category: Podust LM]] |
| - | [[Category: Podust, L M]] | + | [[Category: Podust MV]] |
| - | [[Category: Podust, M V]] | + | [[Category: Von Kries JP]] |
| - | [[Category: 4'-dihydroxybenzophenone complex]] | + | |
| - | [[Category: Alpha-beta]]
| + | |
| - | [[Category: Cyp51-4]]
| + | |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Heme]]
| + | |
| - | [[Category: Heme co-factor]]
| + | |
| - | [[Category: Iron]]
| + | |
| - | [[Category: Lipid synthesis]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Nadp]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Steroid biosynthesis]]
| + | |
| - | [[Category: Sterol biosynthesis]]
| + | |
| Structural highlights
Function
CP51_MYCTU Its precise biological substrate is not known. Catalyzes C14-demethylation of lanosterol, 24,25-dihydrolanosterol and obtusifoliol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
A universal step in the biosynthesis of membrane sterols and steroid hormones is the oxidative removal of the 14alpha-methyl group from sterol precursors by sterol 14alpha-demethylase (CYP51). This enzyme is a primary target in treatment of fungal infections in organisms ranging from humans to plants, and development of more potent and selective CYP51 inhibitors is an important biological objective. Our continuing interest in structural aspects of substrate and inhibitor recognition in CYP51 led us to determine (to a resolution of 1.95A) the structure of CYP51 from Mycobacterium tuberculosis (CYP51(Mt)) co-crystallized with 4,4'-dihydroxybenzophenone (DHBP), a small organic molecule previously identified among top type I binding hits in a library screened against CYP51(Mt). The newly determined CYP51(Mt)-DHBP structure is the most complete to date and is an improved template for three-dimensional modeling of CYP51 enzymes from fungal and prokaryotic pathogens. The structure demonstrates the induction of conformational fit of the flexible protein regions and the interactions of conserved Phe-89 essential for both fungal drug resistance and catalytic function, which were obscure in the previously characterized CYP51(Mt)-estriol complex. DHBP represents a benzophenone scaffold binding in the CYP51 active site via a type I mechanism, suggesting (i) a possible new class of CYP51 inhibitors targeting flexible regions, (ii) an alternative catalytic function for bacterial CYP51 enzymes, and (iii) a potential for hydroxybenzophenones, widely distributed in the environment, to interfere with sterol biosynthesis. Finally, we show the inhibition of M. tuberculosis growth by DHBP in a mouse macrophage model.
X-ray structure of 4,4'-dihydroxybenzophenone mimicking sterol substrate in the active site of sterol 14alpha-demethylase (CYP51).,Eddine AN, von Kries JP, Podust MV, Warrier T, Kaufmann SH, Podust LM J Biol Chem. 2008 May 30;283(22):15152-9. Epub 2008 Mar 26. PMID:18367444[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Aoyama Y, Horiuchi T, Gotoh O, Noshiro M, Yoshida Y. CYP51-like gene of Mycobacterium tuberculosis actually encodes a P450 similar to eukaryotic CYP51. J Biochem. 1998 Oct;124(4):694-6. PMID:9756611
- ↑ Bellamine A, Mangla AT, Nes WD, Waterman MR. Characterization and catalytic properties of the sterol 14alpha-demethylase from Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8937-42. PMID:10430874
- ↑ Eddine AN, von Kries JP, Podust MV, Warrier T, Kaufmann SH, Podust LM. X-ray structure of 4,4'-dihydroxybenzophenone mimicking sterol substrate in the active site of sterol 14alpha-demethylase (CYP51). J Biol Chem. 2008 May 30;283(22):15152-9. Epub 2008 Mar 26. PMID:18367444 doi:10.1074/jbc.M801145200
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