3ua1 | pdb_00003ua1
Crystal structure of the cytochrome P4503A4-bromoergocryptine complex
Structural highlights
Function[CP3A4_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 performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.[1] Publication Abstract from PubMedCytochrome P4503A4 (CYP3A4), a major human drug-metabolizing enzyme, is responsible for the oxidation and clearance of the majority of administered drugs. One of the CYP3A4 substrates is bromoergocryptine (BEC), a dopamine receptor agonist prescribed for the inhibition of prolactin secretion and treatment of Parkinson disease, type 2 diabetes and several other pathological conditions. Here we present a 2.15 Angstrom crystal structure of the CYP3A4-BEC complex where the drug, a type I heme ligand, is bound in a productive mode. The manner of BEC binding is consistent with the in vivo metabolite analysis and identifies the 8 and 9 carbons of the proline ring as the primary sites of oxidation. The crystal structure predicts the importance of Arg212 and Thr224 for binding of the tripeptide and lysergic moieties of BEC, respectively, which we experimentally confirmed. Our data support a three-step BEC binding model, according to which the drug binds first at a peripheral site without perturbing the heme spectrum and then translocates into the active site cavity, where formation of a hydrogen bond between Thr224 and the N1 atom of the lysergic moiety is followed by a slower conformational readjustment of the tripeptide group modulated by Arg212. Structural and mechanistic insights into the interaction of cytochrome P4503A4 with Bromoergocryptine, a type I ligand.,Sevrioukova IF, Poulos TL J Biol Chem. 2011 Dec 7. PMID:22157006[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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