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Structures of human cytochrome P450 1A1 with bergamottin and erlotinib reveal active-site modifications for binding of diverse ligands.

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.

SUBMITTER: Bart AG

PROVIDER: S-EPMC6302172 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Structures of human cytochrome P450 1A1 with bergamottin and erlotinib reveal active-site modifications for binding of diverse ligands.

Bart Aaron G AG Scott Emily E EE

The Journal of biological chemistry 20180925 50

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 poten ...[more]

PMID: 30254074

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Project description:BackgroundMembers of the cytochrome P450 1A family metabolize many procarcinogens such as polycyclicaromatic hydrocarbons and heterocyclic amines. Inactivation of these enzymes is a prerequisite for cancer prevention and treatment in certain cases. Mechanism-based inhibition (time and co-factor dependent) is an effective method for the inactivation of these enzymes. Our recent study on emodin analogs revealed an anthraquinone with ortho-methylarylamine moiety that exhibited timedependent inhibition of P450 enzymes 1A1 and 1A2.MethodsTo determine whether the amino group or the methyl group or both were responsible for the time-dependent inhibition of these enzymes, a set of eleven compounds containing the orthomethylarylamine moiety were identified through a database search, and studied for the inhibition of the P450 enzymes 1A1, 1A2, 2A6 and 2B1. Our earlier studies on carbazole derivatives provided us with highly selective P450 1A2 inhibitors. Glycine scanning studies were performed on the docked proteinligand complexes of compounds 1-20 in order to understand the contribution of different protein residues towards the ligand binding.ResultsFour compounds were found to cause selective time-dependent inhibition of P450 1A1 with KI values ranging from 0.24 to 8.25 mM. These compounds exhibited only direct inhibition of P450 1A2. Molecular modeling studies of these molecules indicated that the shapes of the molecules, their binding modes, and the methyl substituent in close proximity (4.5-5.7 Å) to the heme-Fe all contributed to their selective time-dependent inhibition activity on P450 1A1. Glycine scanning studies for P450 1A1 indicated that ligand interaction with Phe123 was the strongest binding contributor and similar studies for P450 1A2 indicated that ligand interactions with the phenylalanine residues 226 and 260 were the largest binding contributors.ConclusionFour compounds have been identified that exhibit selective time-dependent inhibition of P450 1A1. Modeling studies have indicated that the proximity of the aromatic methyl group to the heme-Fe could be the main contributor for time-dependent inhibition. Future studies will focus on the confirmation of the involvement of the aromatic methyl group in enzyme inactivation.

Dataset Information

Structures of human cytochrome P450 1A1 with bergamottin and erlotinib reveal active-site modifications for binding of diverse ligands.

Publications

Structures of human cytochrome P450 1A1 with bergamottin and erlotinib reveal active-site modifications for binding of diverse ligands.

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