Homology modelling of the enzyme P450 17 alpha-hydroxylase/17,20-lyase--a target for prostate cancer chemotherapy--from the crystal structure of P450BM-3.
Using homology modelling techniques the structure of cytochrome P450 17 alpha-hydroxylase/17-20 lyase (P450c17) has been predicted from the crystal structure of P450BM-3. The resulting structure has been compared to a previous model, built on the basis of homology to P450cam. Despite considerable structural differences between the two template structures, the two derived models for P450c17 show a high degree of similarity in the active-site region. As before, a bilobal active-site cavity is predicted, and we hypothesize that binding of the steroid in one lobe of the active site is associated with the hydroxylase activity of the enzyme, whilst binding in the other is associated with the lyase reaction.
Burke
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DF
CRC Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, UK.
Laughton
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CA
Neidle
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S
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001426:Bacterial Proteins; D001665:Binding Sites; D019475:Camphor 5-Monooxygenase / Q000737:chemistry; D002417:Cattle; D002645:Chickens; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009251:NADPH-Ferrihemoprotein Reductase; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D017433:Protein Structure, Secondary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013254:Steroid 17-alpha-Hydroxylase; D019475:Camphor 5-Monooxygenase; D009251:NADPH-Ferrihemoprotein Reductase; C052423:flavocytochrome P450 BM3 monoxygenases