Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001.
Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001.
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DOI：
10.1038/nature10743
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发表时间：
2012-01-22
期刊：
影响因子：
64.8
通讯作者：
Scott, Emily E.
中科院分区：
文献类型：
--
作者：
DeVore, Natasha M.;Scott, Emily E.
细胞色素P450 17 A1（P450 c17）催化人类雄激素的生物合成。由于前列腺癌细胞对雄激素类固醇反应增殖，因此CYP 17 A1抑制是防止雄激素合成和治疗致命的转移性去势抵抗性前列腺癌的新策略，但药物开发因缺乏CYP 17 A1结构而受到阻碍。在这里，我们报告了CYP 17 A1的唯一已知结构，其中包含阿比特龙，一种最近被FDA批准用于晚期前列腺癌的一流甾体抑制剂，或TOK-001，另一种临床试验中的抑制剂。两者都结合血红素铁，在血红素平面上方形成60°角，紧靠中心I螺旋，3β-OH与F螺旋中的N2 O2相互作用。重要的是，这种结合模式与同源性模型预测的结合模式或与具有已知结构的其他细胞色素P450酶中的类固醇结合模式有很大不同，其中一些特征更类似于类固醇受体。虽然CYP 17 A1的整体结构为理解类固醇生成性疾病患者中发现的许多突变提供了理论基础，但活性位点揭示了多种空间和氢键特征，这将有助于更好地理解酶的双重羟化酶和裂解酶催化能力，并有助于合理的药物设计。具体而言，基于结构的设计有望帮助开发仅结合CYP 17 A1并仅抑制其雄激素生成裂解酶活性的抑制剂，以改善前列腺和其他前列腺癌反应性癌症的治疗。
Cytochrome P450 17A1 (P450c17) catalyzes the biosynthesis of androgens in humans. Since prostate cancer cells proliferate in response to androgen steroids, CYP17A1 inhibition is a new strategy to prevent androgen synthesis and treat lethal metastatic castration-resistant prostate cancer, but drug development has been hampered by the lack of a CYP17A1 structure. Here we report the only known structures of CYP17A1, which contain either abiraterone, a first-in-class steroidal inhibitor recently approved by the FDA for late-stage prostate cancer, or TOK-001, another inhibitor in clinical trials. Both bind the heme iron forming a 60° angle above the heme plane, packing against the central I helix with the 3β-OH interacting with N202 in the F helix. Importantly, this binding mode differs substantially from those predicted by homology models or from steroids in other cytochrome P450 enzymes with known structures, with some features more similar to steroid receptors. While the overall CYP17A1 structure provides a rationale for understanding many mutations found in patients with steroidogenic diseases, the active site reveals multiple steric and hydrogen bonding features that will facilitate 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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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
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作者：
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影响因子：
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作者：
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Hartmann, Rolf W.
影响因子：
4.8
作者：
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通讯作者：
Miller, WL
影响因子：
5.8
作者：
Ergun-Longmire, Berrin;Auchus, Richard;New, Maria I.
通讯作者：
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