3pm0
From Proteopedia
Structural Characterization of the Complex between Alpha-Naphthoflavone and Human Cytochrome P450 1B1 (CYP1B1)
Structural highlights
Disease[CP1B1_HUMAN] Peters anomaly;Congenital glaucoma;Primary adult open-angle glaucoma;Juvenile glaucoma. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. CYP1B1 mutations have been reported to pose a significant risk for early-onset POAG and also modify glaucoma phenotype in patients who do not carry a MYOC mutation (PubMed:15342693).[1] The gene represented in this entry acts as a disease modifier. Digenic mutations in CYP1B1 and MYOC have been found in a family segregating both primary adult-onset and juvenile forms of open angle glaucoma (PubMed:11774072). All affected family members with mutations in both MYOC and CYP1B1 had juvenile glaucoma, whereas those with only the MYOC mutation had the adult-onset form (PubMed:11774072).[2] Function[CP1B1_HUMAN] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, retinoid and xenobiotics. Preferentially oxidizes 17beta-estradiol to the carcinogenic 4-hydroxy derivative, and a variety of procarcinogenic compounds to their activated forms, including polycyclic aromatic hydrocarbons. Promotes angiogenesis by removing cellular oxygenation products, thereby decreasing oxidative stress, release of antiangiogenic factor THBS2, then allowing endothelial cells migration, cell adhesion and capillary morphogenesis. These changes are concommitant with the endothelial nitric oxide synthase activity and nitric oxide synthesis. Plays an important role in the regulation of perivascular cell proliferation, migration, and survival through modulation of the intracellular oxidative state and NF-kappa-B expression and/or activity, during angiogenesis. Contributes to oxidative homeostasis and ultrastructural organization and function of trabecular meshwork tissue through modulation of POSTN expression.[3] [4] [5] [6] Publication Abstract from PubMedThe atomic structure of human P450 1B1 was determined by x-ray crystallography to 2.7A resolution with alpha-naphthoflavone (ANF) bound in the active site cavity. Although the amino acid sequences of human P450s 1B1 and 1A2 have diverged significantly, both enzymes exhibit narrow active site cavities, which underlie similarities in their substrate profiles. Helix I residues adopt a relatively flat conformation in both enzymes, and a characteristic distortion of helix F places Phe231 in 1B1 and Phe226 in 1A2 in similar positions for pi-$[pi] stacking with ANF. ANF binds in a distinctly different orientation in P450 1B1 from that observed for 1A2. This reflects, in part, divergent conformations of the helix B-C loop that are stabilized by different hydrogen bonding interactions in the two enzymes. Additionally, differences between the two enzymes for other amino acids that line the edges of the cavity contribute to distinct orientations of ANF in the two active sites. Thus, the narrow cavity is conserved in both P450 subfamily 1A and 1B with sequence divergence around the edges of the cavity that modify substrate and inhibitor binding. The conservation of these P450 1B1 active site amino acid residues across vertebrate species suggests that these structural features are conserved. Structural characterization of the complex between {alpha}-naphthoflavone and human cytochrome P450 1B1.,Wang A, Savas U, Stout CD, Johnson EF J Biol Chem. 2010 Dec 8. PMID:21147782[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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