title: A three-dimensional model of CYP19 aromatase for structure-based drug design.
abstract: Aromatase (CYP450(arom), CYP19) is an enzyme responsible for converting the aliphatic androgens androstenedione and testosterone to the aromatic estrogens estrone and estradiol, respectively. These endogenous hormones are a key factor in cancer tumor formation and proliferation through a cascade starting from estrogen binding to estrogen receptor. To interfere with the overproduction of estrogens especially in tumor tissue, it is possible to inhibit aromatase activity. This can be achieved using aromatase inhibitors. In order to design novel aromatase inhibitors, it is necessary to have an understanding of the active site of aromatase. As no crystal structure of the enzyme has yet been published, we built a homology model of aromatase using the first crystallized mammalian cytochrome enzyme, rabbit 21-progesterone hydroxylase 2C5, as a template structure. The initial model was validated with exhaustive molecular dynamics simulation with and without the natural substrate androstenedione. The resulting enzyme-substrate complex shows very good stability and only two of the residues are in disallowed regions in a Ramachandran plot.
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, Faculty of Science, P.O. Box 55, University of Helsinki, FIN-00014, Finland.
authors.forename: Sampo
authors.initials: S
authors.lastname: Karkola
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Höltje
authors.forename: Kristiina
authors.initials: K
authors.lastname: Wähälä
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001141:Aromatase / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D001141:Aromatase