6dwn | pdb_00006dwn

Structure of Human Cytochrome P450 1A1 with Erlotinib

spinqualitylabelsall models 6dwn, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6dwn is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Ligands: AQ4, CPS, HEM Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CP1A1_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, and xenobiotics. Publication Abstract from PubMed Human cytochrome P450 1A1 (CYP1A1) is an extrahepatic enzyme involved in the monooxygenation of structurally-diverse compounds ranging from natural products to drugs and protoxins. Because CYP1A1 has a role in human carcinogenesis, inhibiting its activity may potentially aid in cancer chemoprevention, whereas utilizing CYP1A1's oxidative activity could help selectively activate anticancer prodrugs. Such potential therapeutic purposes require detailed knowledge of CYP1A1's interactions with potential ligands. Known CYP1A1 ligands also vary substantially in size and it has not been apparent from a single existing CYP1A1 structure how larger, structurally diverse ligands are accommodated within the enclosed active site. Here, two new X-ray structures with the natural product furanocoumarin bergamottin (2.85 A) and the lung cancer drug erlotinib (3.0 A resolution) revealed binding orientations consistent with the formation of innocuous metabolites and of toxic metabolites, respectively. They also disclosed local changes in the roof of the active site that enlarge the active site and ultimately form a channel to the protein exterior. Although further structural modifications would be required to accommodate the largest CYP1A1 ligands, knowing which components of the active site are malleable provides powerful information for those attempting to use computational approaches to predict compound binding and substrate metabolism by this clinically relevant monooxygenase. Structures of human cytochrome P450 1A1 with bergamottin and erlotinib reveal active-site modifications for binding of diverse ligands.,Bart AG, Scott EE J Biol Chem. 2018 Sep 25. pii: RA118.005588. doi: 10.1074/jbc.RA118.005588. PMID:30254074 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cytochrome P450 3D structures

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