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Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001


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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Figure 1: Function of CYP17A1 and inhibition by clinical compounds.
Figure 2: CYP17A1 ligand binding.
Figure 3: Hydrogen bond network with abiraterone.
Figure 4: CYP17A1 compared to the androgen receptor and CYP11A1.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

Atomic coordinates and structure factors for the reported crystal structures have been deposited with the Protein Data Bank under the accession codes 3RUK for CYP17A1 with abiraterone and 3SWZ for CYP17A1 with TOK-001.


  1. Miller, W. L. & Auchus, R. J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Rev. 32, 81–151 (2011)

    CAS  Article  Google Scholar 

  2. Attard, G., Reid, A. H., Olmos, D. & de Bono, J. S. Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven. Cancer Res. 69, 4937–4940 (2009)

    CAS  Article  Google Scholar 

  3. Yap, T. A., Carden, C. P., Attard, G. & de Bono, J. S. Targeting CYP17: Established and novel approaches in prostate cancer. Curr. Opin. Pharmacol. 8, 449–457 (2008)

    CAS  Article  Google Scholar 

  4. Vasaitis, T. S., Bruno, R. D. & Njar, V. C. CYP17 inhibitors for prostate cancer therapy. J. Steroid Biochem. Mol. Biol. 125, 23–31 (2011)

    CAS  Article  Google Scholar 

  5. de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011)

    CAS  Article  Google Scholar 

  6. Molina, A. & Belidegrun, A. Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling. J. Urol. 185, 787–794 (2011)

    CAS  Article  Google Scholar 

  7. Auchus, R. J., Geller, D. H., Lee, T. C. & Miller, W. L. The regulation of human P450c17 activity: relationship to premature adrenarche, insulin resistance and the polycystic ovary syndrome. Trends Endocrinol. Metab. 9, 47–50 (1998)

    CAS  Article  Google Scholar 

  8. Attard, G. et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J. Clin. Oncol. 26, 4563–4571 (2008)

    CAS  Article  Google Scholar 

  9. Brodie, A., Njar, V., Macedo, L. F., Vasitis, T. S. & Sabnis, G. The Coffey Lecture: steroidogenic enzyme inhibitors and hormone dependent cancer. Urol. Oncol. 27, 53–63 (2009)

    CAS  Article  Google Scholar 

  10. Imai, T. et al. Expression and purification of functional human 17α-hydroxylase/17,20-lyase (P450c17) in Escherichia coli. Use of this system for study of a novel form of combined 17α-hydroxylase/17,20-lyase deficiency. J. Biol. Chem. 268, 19681–19689 (1993)

    CAS  PubMed  Google Scholar 

  11. Huang, P., Chandra, V. & Rastinejad, F. Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu. Rev. Physiol. 72, 247–272 (2010)

    CAS  Article  Google Scholar 

  12. Pereira de Jésus-Tran, K. et al. Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity. Protein Sci. 15, 987–999 (2006)

    Article  Google Scholar 

  13. Vasaitis, T. et al. Androgen receptor inactivation contributes to antitumor efficacy of 17α-hydroxylase/17,20-lyase inhibitor 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol. Cancer Ther. 7, 2348–2357 (2008)

    CAS  Article  Google Scholar 

  14. Ghosh, D., Griswold, J., Erman, M. & Pangborn, W. Structural basis for androgen specificity and oestrogen synthesis in human aromatase. Nature 457, 219–223 (2009)

    ADS  CAS  Article  Google Scholar 

  15. Mast, N. et al. Structural basis for three-step sequential catalysis by the cholesterol side chain cleavage enzyme CYP11A1. J. Biol. Chem. 286, 5607–5613 (2011)

    CAS  Article  Google Scholar 

  16. Mast, N. et al. Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc. Natl Acad. Sci. USA 105, 9546–9551 (2008)

    ADS  CAS  Article  Google Scholar 

  17. Dhir, V. et al. Steroid 17α-hydroxylase deficiency: Functional characterization of four mutations (A174E, V178D, R440C, L465P) in the CYP17A1 gene. J. Clin. Endocrinol. Metab. 94, 3058–3064 (2009)

    CAS  Article  Google Scholar 

  18. Rosa, S. et al. Clinical, genetic and functional characteristics of three novel CYP17A1 mutations causing combined 17α-hydroxylase/17,20-lyase deficiency. Horm. Res. Paediatr. 73, 198–204 (2010)

    CAS  Article  Google Scholar 

  19. Katsumata, N., Ogawa, E., Fujiwara, I. & Fujikura, K. Novel CYP17A1 mutation in a Japanese patient with combined 17α-hydroxylase/17,20-lyase deficiency. Metabolism 59, 275–278 (2010)

    CAS  Article  Google Scholar 

  20. Ergun-Longmire, B. et al. Two novel mutations found in a patient with 17α-hydroxylase enzyme deficiency. J. Clin. Endocrinol. Metab. 91, 4179–4182 (2006)

    CAS  Article  Google Scholar 

  21. Sahakitrungruang, T., Tee, M. K., Speiser, P. W. & Miller, W. L. Novel P450c17 mutation H373D causing combined 17α-hydroxylase/17,20-lyase deficiency. J. Clin. Endocrinol. Metab. 94, 3089–3092 (2009)

    CAS  Article  Google Scholar 

  22. Biason-Lauber, A. et al. 17α-hydroxylase/17,20-lyase deficiency as a model to study enzymatic activity regulation: role of phosphorylation. J. Clin. Endocrinol. Metab. 85, 1226–1231 (2000)

    CAS  PubMed  Google Scholar 

  23. Lee-Robichaud, P. et al. The cationic charges on Arg347, Arg358 and Arg449 of human cytochrome P450c17 (CYP17) are essential for the enzyme's cytochrome b5-dependent acyl-carbon cleavage activities. J. Steroid Biochem. Mol. Biol. 92, 119–130 (2004)

    CAS  Article  Google Scholar 

  24. Gupta, M. K., Geller, D. H. & Auchus, R. J. Pitfalls in characterizing P450c17 mutations associated with isolated 17,20-lyase deficiency. J. Clin. Endocrinol. Metab. 86, 4416–4423 (2001)

    CAS  Article  Google Scholar 

  25. Tiosano, D. et al. Metabolic evidence for impaired 17α-hydroxylase activity in a kindred bearing the E305G mutation for isolate 17,20-lyase activity. Eur. J. Endocrinol. 158, 385–392 (2008)

    CAS  Article  Google Scholar 

  26. Auchus, R. J., Lee, T. C. & Miller, W. L. Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer. J. Biol. Chem. 273, 3158–3165 (1998)

    CAS  Article  Google Scholar 

  27. Swart, A. C., Storbeck, K. H. & Swart, P. A single amino acid residue, Ala 105, confers 16α-hydroxylase activity to human cytochrome P450 17α-hydroxylase/17,20 lyase. J. Steroid Biochem. Mol. Biol. 119, 112–120 (2010)

    CAS  Article  Google Scholar 

  28. Haider, S. M., Patel, J. S., Poojari, C. S. & Neidle, S. Molecular modeling on inhibitor complexes and active-site dynamics of cytochrome P450 C17, a target for prostate cancer therapy. J. Mol. Biol. 400, 1078–1098 (2010)

    CAS  Article  Google Scholar 

  29. Jagusch, C. et al. Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17). Part I: heterocyclic modifications of the core structure. Bioorg. Med. Chem. 16, 1992–2010 (2008)

    CAS  Article  Google Scholar 

  30. Pechurskaya, T. A., Lukashevich, O. P., Gilep, A. A. & Usanov, S. A. Engineering, expression, and purification of “soluble” human cytochrome P45017α and its functional characterization. Biochemistry 73, 806–811 (2008)

    CAS  PubMed  Google Scholar 

  31. Leslie, A. G. W. MOSFLM 6.0 (Cambridge, 1998)

  32. Collaborative Computational Project, 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994)

    Article  Google Scholar 

  33. Long, F., Vagin, A. A., Young, P. & Murshudov, G. N. BALBES: a molecular replacement pipeline. Acta Crystallogr. D 64, 125–132 (2008)

    CAS  Article  Google Scholar 

  34. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)

    Article  Google Scholar 

  35. Murshudov, G. N., Vagin, A. A. & Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D 53, 240–255 (1997)

    CAS  Article  Google Scholar 

  36. Hooft, R. W., Vriend, G., Sander, C. & Abola, E. E. Errors in protein structures. Nature 381, 272 (1996)

    ADS  CAS  Article  Google Scholar 

  37. Laskowski, R. A., MacArthur, M. W., Moss, D. S. & Thornton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26, 283–291 (1993)

    CAS  Article  Google Scholar 

  38. DeVore, N. M. et al. Key residues controlling binding of diverse ligands to human cytochrome P450 2A enzymes. Drug Metab. Dispos. 37, 1319–1327 (2009)

    CAS  Article  Google Scholar 

  39. DeLano, W. L. The PyMol Molecular Graphics System (DeLano Scientific, 2002)

    Google Scholar 

  40. Kleywegt, G. J. & Jones, T. A. Detection, delineation, measurement and display of cavities in macromolecular structures. Acta Crystallogr. D 50, 178–185 (1994)

    CAS  Article  Google Scholar 

  41. Jain, A. N. Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. J. Med. Chem. 46, 499–511 (2003)

    CAS  Article  Google Scholar 

  42. Hutschenreuter, T. U., Ehmer, P. B. & Hartmann, R. W. Synthesis of hydroxy derivatives of highly potent non-steroidal CYP 17 inhibitors as potential metabolites and evaluation of their activity by a non cellular assay using recombinant human enzyme. J. Enzyme Inhib. Med. Chem. 19, 17–32 (2004)

    CAS  Article  Google Scholar 

  43. Shen, A. L., Porter, T. D., Wilson, T. E. & Kasper, C. B. Structural analysis of the FMN binding domain of NADPH-cytochrome P-450 oxidoreductase by site-directed mutagenesis. J. Biol. Chem. 264, 7584–7589 (1989)

    CAS  PubMed  Google Scholar 

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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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Correspondence to Emily E. Scott.

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The authors declare no competing financial interests.

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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).

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