Abstract
Cytochrome P450 17A1 (also known as CYP17A1 and cytochrome P450c17) catalyses the biosynthesis of androgens in humans1. As prostate cancer cells proliferate in response to androgen steroids2,3, CYP17A1 inhibition is a new strategy to prevent androgen synthesis and treat lethal metastatic castration-resistant prostate cancer4, but drug development has been hampered by lack of information regarding the structure of CYP17A1. Here we report X-ray crystal structures of CYP17A1, which were obtained in the presence of either abiraterone, a first-in-class steroidal inhibitor recently approved by the US Food and Drug Administration for late-stage prostate cancer5, or TOK-001, an inhibitor that is currently undergoing clinical trials4,6. Both of these inhibitors bind the haem iron, forming a 60° angle above the haem plane and packing against the central I helix with the 3β-OH interacting with aspargine 202 in the F helix. Notably, this binding mode differs substantially from those that are predicted by homology models and from steroids in other cytochrome P450 enzymes with known structures, and some features of this binding mode are more similar to steroid receptors. Whereas the overall structure of CYP17A1 provides a rationale for understanding many mutations that are found in patients with steroidogenic diseases, the active site reveals multiple steric and hydrogen bonding features that will facilitate a better understanding of the enzyme’s dual hydroxylase and lyase catalytic capabilities and assist in rational drug design. Specifically, structure-based design is expected to aid development of inhibitors that bind only CYP17A1 and solely inhibit its androgen-generating lyase activity to improve treatment of prostate and other hormone-responsive cancers.
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Acknowledgements
X-ray data were collected at the Stanford Synchrotron Radiation Lightsource (SSRL). The SSRL Structural Molecular Biology Program is supported by the US Department of Energy Office of Biological and Environmental Research and by the US National Institutes of Health (NIH), National Center for Research Resources, Biomedical Technology Program and the National Institute of General Medical Sciences. We thank C.-J. Liu and the University of Kansas (KU) Center of Biomedical Research Excellence (COBRE) Center for Cancer Experimental Therapeutics for synthesizing abiraterone (NIH RR030926), M. R. Waterman for the full-length CYP17A1 construct, J. Wang for assistance with the Fe(iv) = O construct used in docking and A. Skinner and J. Aubé for manuscript suggestions. This research was funded by the NIH through the KU COBRE Center for Protein Structure and Function (NIH RR17708) and GM076343.
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Author Contributions N.M.D. engineered, expressed, characterized, purified and crystallized CYP17A1 under the direction of E.E.S. N.M.D. and E.E.S. jointly performed X-ray diffraction experiments, solved and refined the structures, and wrote the manuscript. N.M.D. performed the docking studies of CYP17A1.
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DeVore, N., Scott, E. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature 482, 116–119 (2012). https://doi.org/10.1038/nature10743
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DOI: https://doi.org/10.1038/nature10743
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