Abstract
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 (at 2.85 Å resolution) and the lung cancer drug erlotinib (3.0 Å) 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.
Highlights
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
This study describes two novel CYP1A1 structures, one with the epidermal growth factor receptor (EGFR) inhibitor erlotinib used in anticancer therapy and another with the furanocoumarin P450 inhibitor bergamottin
The active-site cavity for the CYP1A1/ANF structure conforms to these aspects, but it is not helpful in discerning how other CYP1A1 ligands with larger sizes and/or varying dimensions are accommodated by the active site
Summary
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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A single crystal structure of CYP1A1 was previously determined, in complex with the small-molecule inhibitor ␣-naphthoflavone (ANF) [7] This structure revealed a narrow and closed active site not much larger than the ANF ligand itself. A number of known 1A1 substrates and inhibitors reported in the literature reveal substrate and inhibitor sizes and geometries that are not compatible with the dimensions of the currently defined CYP1A1/ANF active site
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call