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3iw1

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Revision as of 08:15, 1 November 2017

Crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP125 in complex with androstenedione

Structural highlights

3iw1 is a 1 chain structure with sequence from Myctu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	3ivy, 3iw0, 2iw2
Gene:	cyp125, MT3649, MTCY03C7.11, Rv3545c (MYCTU)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CP125_MYCTU] Catalyzes the C-27 hydroxylation of cholest-4-en-3-one and cholesterol and subsequently oxidizes the alcohol of the former to the cholest-4-en-3-one-27-oic acid via the aldehyde intermediate. Not required to incorporate the cholesterol side-chain carbon atoms into cellular lipids.^[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

We report characterization and the crystal structure of the Mycobacterium tuberculosis cytochrome P450 CYP125, a P450 implicated in metabolism of host cholesterol and essential for establishing infection in mice. CYP125 is purified in a high spin form and undergoes both type I and II spectral shifts with various azole drugs. The 1.4-A structure of ligand-free CYP125 reveals a "letterbox" active site cavity of dimensions appropriate for entry of a polycyclic sterol. A mixture of hexa-coordinate and penta-coordinate states could be discerned, with water binding as the 6th heme-ligand linked to conformation of the I-helix Val(267) residue. Structures in complex with androstenedione and the antitubercular drug econazole reveal that binding of hydrophobic ligands occurs within the active site cavity. Due to the funnel shape of the active site near the heme, neither approaches the heme iron. A model of the cholesterol CYP125 complex shows that the alkyl side chain extends toward the heme iron, predicting hydroxylation of cholesterol C27. The alkyl chain is in close contact to Val(267), suggesting a substrate binding-induced low- to high-spin transition coupled to reorientation of the latter residue. Reconstitution of CYP125 activity with a redox partner system revealed exclusively cholesterol 27-hydroxylation, consistent with structure and modeling. This activity may enable catabolism of host cholesterol or generation of immunomodulatory compounds that enable persistence in the host. This study reveals structural and catalytic properties of a potential M. tuberculosis drug target enzyme, and the likely mode by which the host-derived substrate is bound and hydroxylated.

The Structure of Mycobacterium tuberculosis CYP125: molecular basis for cholesterol binding in a P450 needed for host infection.,McLean KJ, Lafite P, Levy C, Cheesman MR, Mast N, Pikuleva IA, Leys D, Munro AW J Biol Chem. 2009 Dec 18;284(51):35524-33. Epub . PMID:19846552^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Capyk JK, Kalscheuer R, Stewart GR, Liu J, Kwon H, Zhao R, Okamoto S, Jacobs WR Jr, Eltis LD, Mohn WW. Mycobacterial cytochrome p450 125 (cyp125) catalyzes the terminal hydroxylation of c27 steroids. J Biol Chem. 2009 Dec 18;284(51):35534-42. doi: 10.1074/jbc.M109.072132. Epub . PMID:19846551 doi:http://dx.doi.org/10.1074/jbc.M109.072132
↑ Ouellet H, Guan S, Johnston JB, Chow ED, Kells PM, Burlingame AL, Cox JS, Podust LM, de Montellano PR. Mycobacterium tuberculosis CYP125A1, a steroid C27 monooxygenase that detoxifies intracellularly generated cholest-4-en-3-one. Mol Microbiol. 2010 Aug;77(3):730-42. Epub 2010 Jun 10. PMID:20545858 doi:10.1111/j.1365-2958.2010.07243.x
↑ McLean KJ, Lafite P, Levy C, Cheesman MR, Mast N, Pikuleva IA, Leys D, Munro AW. The Structure of Mycobacterium tuberculosis CYP125: molecular basis for cholesterol binding in a P450 needed for host infection. J Biol Chem. 2009 Dec 18;284(51):35524-33. Epub . PMID:19846552 doi:10.1074/jbc.M109.032706

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3iw1"

@@ Line 1: / Line 1: @@
 ==Crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP125 in complex with androstenedione==
 <StructureSection load='3iw1' size='340' side='right' caption='[[3iw1]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ivy|3ivy]], [[3iw0|3iw0]], [[2iw2|2iw2]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">cyp125, MT3649, MTCY03C7.11, Rv3545c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</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=3iw1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3iw1 OCA], [http://pdbe.org/3iw1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3iw1 RCSB], [http://www.ebi.ac.uk/pdbsum/3iw1 PDBsum]</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=3iw1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3iw1 OCA], [http://pdbe.org/3iw1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3iw1 RCSB], [http://www.ebi.ac.uk/pdbsum/3iw1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3iw1 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 29: / Line 30: @@
 </div>
 <div class="pdbe-citations 3iw1" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Cytochrome P450|Cytochrome P450]]
 == References ==
 <references/>

3iw1

From Proteopedia

Revision as of 08:15, 1 November 2017

Crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP125 in complex with androstenedione

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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