2vku

From Proteopedia

(Difference between revisions)

Current revision

4,4'-Dihydroxybenzophenone Mimics Sterol Substrate in the Binding Site of Sterol 14alpha-Demethylase (CYP51) in the X-ray Structure of the Complex

Structural highlights

2vku is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.95Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2vku"

@@ Line 1: / Line 1: @@
-{{Seed}}
-[[Image:2vku.png|left|200px]]
-<!--
+==4,4'-Dihydroxybenzophenone Mimics Sterol Substrate in the Binding Site of Sterol 14alpha-Demethylase (CYP51) in the X-ray Structure of the Complex==
-The line below this paragraph, containing "STRUCTURE_2vku", creates the "Structure Box" on the page.
+<StructureSection load='2vku' size='340' side='right'caption='[[2vku]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<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>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</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>
-{{STRUCTURE_2vku|  PDB=2vku  |  SCENE=  }}
+<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>
+</table>
+== Function ==
+[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 ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vk/2vku_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2vku ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== 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.
-===4,4'-DIHYDROXYBENZOPHENONE MIMICS STEROL SUBSTRATE IN THE BINDING SITE OF STEROL 14ALPHA-DEMETHYLASE (CYP51) IN THE X-RAY STRUCTURE OF THE COMPLEX===
+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<ref>PMID:18367444</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2vku" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_18367444}}, adds the Publication Abstract to the page
+*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
-(as it appears on PubMed at http://www.pubmed.gov), where 18367444 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_18367444}}
+__TOC__
+</StructureSection>
-==About this Structure==
+[[Category: Large Structures]]
-VKU is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VKU OCA].
+[[Category: Mycobacterium tuberculosis H37Rv]]
+[[Category: Eddine AN]]
-==Reference==
+[[Category: Podust LM]]
-X-ray Structure of 4,4'-Dihydroxybenzophenone Mimicking Sterol Substrate in the Active Site of Sterol 14{alpha}-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:[http://www.ncbi.nlm.nih.gov/pubmed/18367444 18367444]
+[[Category: Podust MV]]
-[[Category: Mycobacterium tuberculosis]]
+[[Category: Von Kries JP]]
-[[Category: Single protein]]
-[[Category: Sterol 14-demethylase]]
-[[Category: Eddine, A N.]]
-[[Category: Kries, J P.Von.]]
-[[Category: Podust, L M.]]
-[[Category: Podust, M V.]]
-[[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]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 15:57:36 2008''

2vku

From Proteopedia

Current revision

4,4'-Dihydroxybenzophenone Mimics Sterol Substrate in the Binding Site of Sterol 14alpha-Demethylase (CYP51) in the X-ray Structure of the Complex

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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