3UA1
Crystal structure of the cytochrome P4503A4-bromoergocryptine complex
Summary for 3UA1
| Entry DOI | 10.2210/pdb3ua1/pdb |
| Related | 1TQN 2JOD 2VOM 3NXU |
| Descriptor | Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, bromoergocryptine, ... (4 entities in total) |
| Functional Keywords | protein-substrate complex, monooxygenase, cytochrome p450 reductase, cytochrome b5, membrane, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Cellular location | Endoplasmic reticulum membrane; Single-pass membrane protein: P08684 |
| Total number of polymer chains | 1 |
| Total formula weight | 57028.89 |
| Authors | Sevrioukova, I.F.,Poulos, T.L. (deposition date: 2011-10-20, release date: 2011-12-14, Last modification date: 2023-09-13) |
| Primary citation | Sevrioukova, I.F.,Poulos, T.L. Structural and Mechanistic Insights into the Interaction of Cytochrome P4503A4 with Bromoergocryptine, a Type I Ligand. J.Biol.Chem., 287:3510-3517, 2012 Cited by PubMed Abstract: Cytochrome 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 Å crystal structure of the CYP3A4-BEC complex in which 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 Arg(212) and Thr(224) for binding of the tripeptide and lysergic moieties of BEC, respectively, which we confirmed experimentally. 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 Thr(224) and the N1 atom of the lysergic moiety is followed by a slower conformational readjustment of the tripeptide group modulated by Arg(212). PubMed: 22157006DOI: 10.1074/jbc.M111.317081 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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