1ea1

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==Overview==
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{{ABSTRACT_11248033}}
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Cytochrome P450 14alpha-sterol demethylases (CYP51) are essential enzymes in sterol biosynthesis in eukaryotes. CYP51 removes the 14alpha-methyl group from sterol precursors such as lanosterol, obtusifoliol, dihydrolanosterol, and 24(28)-methylene-24,25-dihydrolanosterol. Inhibitors of CYP51 include triazole antifungal agents fluconazole and itraconazole, drugs used in treatment of topical and systemic mycoses. The 2.1- and 2.2-A crystal structures reported here for 4-phenylimidazole- and fluconazole-bound CYP51 from Mycobacterium tuberculosis (MTCYP51) are the first structures of an authentic P450 drug target. MTCYP51 exhibits the P450 fold with the exception of two striking differences-a bent I helix and an open conformation of BC loop-that define an active site-access channel running along the heme plane perpendicular to the direction observed for the substrate entry in P450BM3. Although a channel analogous to that in P450BM3 is evident also in MTCYP51, it is not open at the surface. The presence of two different channels, with one being open to the surface, suggests the possibility of conformationally regulated substrate-in/product-out openings in CYP51. Mapping mutations identified in Candida albicans azole-resistant isolates indicates that azole resistance in fungi develops in protein regions involved in orchestrating passage of CYP51 through different conformational stages along the catalytic cycle rather than in residues directly contacting fluconazole. These new structures provide a basis for rational design of new, more efficacious antifungal agents as well as insight into the molecular mechanism of P450 catalysis.
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==About this Structure==
==About this Structure==
1EA1 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. The following page contains interesting information on the relation of 1EA1 with [[http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb82_1.html Cytochrome p450]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EA1 OCA].
1EA1 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. The following page contains interesting information on the relation of 1EA1 with [[http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb82_1.html Cytochrome p450]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EA1 OCA].
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==Reference==
 
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Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors., Podust LM, Poulos TL, Waterman MR, Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3068-73. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11248033 11248033]
 
[[Category: Cytochrome p450]]
[[Category: Cytochrome p450]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Mycobacterium tuberculosis]]
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[[Category: Azole inhibitor]]
[[Category: Azole inhibitor]]
[[Category: Cytochrome p450]]
[[Category: Cytochrome p450]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 14:51:14 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jun 26 17:13:01 2008''

Revision as of 14:13, 26 June 2008

Image:1ea1.png

Template:STRUCTURE 1ea1

CYTOCHROME P450 14 ALPHA-STEROL DEMETHYLASE (CYP51) FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH FLUCONAZOLE


Template:ABSTRACT 11248033

About this Structure

1EA1 is a Single protein structure of sequence from Mycobacterium tuberculosis. The following page contains interesting information on the relation of 1EA1 with [Cytochrome p450]. Full crystallographic information is available from OCA.

Page seeded by OCA on Thu Jun 26 17:13:01 2008

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