title: Three-dimensional model of cytochrome P450 human aromatase.
abstract: A three-dimensional (3-D) structure of human aromatase (CYP 19) was modeled on the basis of the crystal structure of rabbit CYP2C5, the first solved X-ray structure of an eukaryotic cytochrome P450 and was evaluated by docking S-fadrozole and the steroidal competitive inhibitor (19R)-10-thiiranylestr-4-ene-3,17-dione, into the enzyme active site. According to a previous pharmacophoric hypothesis described in the literature, the cyano group of S-fadrozole partially mimics the steroid backbone C(17) carbonyl group of (19R)-10-thiiranylestr-4-ene-3,17-dione, and was oriented in a favorable position for H-bonding with the newly identified positively charged residues Lys 119 and Arg435. In addition, this model is consistent with the recent combined mutagenesis/modeling studies already published concerning the roles ofAsp309 and His480 in the aromatization of the steroid A ring.
authors.affiliation: Department de Pharmacochimie, Biomolecules et Cibles Thérapeutiques, UPRES EA1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, F-44035 Nantes cedex 1, France. cedric.loge@univ-nantes.fr
authors.forename: Cedric
authors.initials: C
authors.lastname: Loge
authors.forename: Marc
authors.initials: M
authors.lastname: Le Borgne
authors.forename: Pascal
authors.initials: P
authors.lastname: Marchand
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Robert
authors.forename: Guillaume
authors.initials: G
authors.lastname: Le Baut
authors.forename: Martina
authors.initials: M
authors.lastname: Palzer
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001141:Aromatase / Q000737:chemistry* / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004963:Estrenes / Q000737:chemistry* / Q000494:pharmacology; D017316:Fadrozole / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011817:Rabbits; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004963:Estrenes; C051665:10-thiirane-4-estrene-3,17-dione; D001141:Aromatase; D017316:Fadrozole