2bdm: Difference between revisions
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'''Structure of Cytochrome P450 2B4 with Bound Bifonazole''' | '''Structure of Cytochrome P450 2B4 with Bound Bifonazole''' | ||
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[[Category: White, M A.]] | [[Category: White, M A.]] | ||
[[Category: Zhao, Y.]] | [[Category: Zhao, Y.]] | ||
[[Category: | [[Category: Cyp 2b4]] | ||
[[Category: | [[Category: Cyp lm2]] | ||
[[Category: | [[Category: Membrane protein]] | ||
[[Category: | [[Category: Monooxygenase]] | ||
[[Category: | [[Category: Oxidoreductase]] | ||
[[Category: | [[Category: P450]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 20:08:44 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 17:08, 3 May 2008
Structure of Cytochrome P450 2B4 with Bound Bifonazole
Overview
To better understand ligand-induced structural transitions in cytochrome P450 2B4, protein-ligand interactions were investigated using a bulky inhibitor. Bifonazole, a broad spectrum antifungal agent, inhibits monooxygenase activity and induces a type II binding spectrum in 2B4dH(H226Y), a modified enzyme previously crystallized in the presence of 4-(4-chlorophenyl)imidazole (CPI). Isothermal titration calorimetry and tryptophan fluorescence quenching indicate no significant burial of protein apolar surface nor altered accessibility of Trp-121 upon bifonazole binding, in contrast to recent results with CPI. A 2.3 A crystal structure of 2B4-bifonazole reveals a novel open conformation with ligand bound in the active site, which is significantly different from either the U-shaped cleft of ligand-free 2B4 or the small active site pocket of 2B4-CPI. The O-shaped active site cleft of 2B4-bifonazole is widely open in the middle but narrow at the top. A bifonazole molecule occupies the bottom of the active site cleft, where helix I is bent approximately 15 degrees to accommodate the bulky ligand. The structure also defines unanticipated interactions between helix C residues and bifonazole, suggesting an important role of helix C in azole recognition by mammalian P450s. Comparison of the ligand-free 2B4 structure, the 2B4-CPI structure, and the 2B4-bifonazole structure identifies structurally plastic regions that undergo correlated conformational changes in response to ligand binding. The most plastic regions are putative membrane-binding motifs involved in substrate access or substrate binding. The results allow us to model the membrane-associated state of P450 and provide insight into how lipophilic substrates access the buried active site.
About this Structure
2BDM is a Single protein structure of sequence from Oryctolagus cuniculus. Full crystallographic information is available from OCA.
Reference
Structure of microsomal cytochrome P450 2B4 complexed with the antifungal drug bifonazole: insight into P450 conformational plasticity and membrane interaction., Zhao Y, White MA, Muralidhara BK, Sun L, Halpert JR, Stout CD, J Biol Chem. 2006 Mar 3;281(9):5973-81. Epub 2005 Dec 21. PMID:16373351 Page seeded by OCA on Sat May 3 20:08:44 2008
