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Crystal structure of steroid reductase SRD5A reveals conserved steroid reduction mechanism.
Han, Yufei; Zhuang, Qian; Sun, Bo; Lv, Wenping; Wang, Sheng; Xiao, Qingjie; Pang, Bin; Zhou, Youli; Wang, Fuxing; Chi, Pengliang; Wang, Qisheng; Li, Zhen; Zhu, Lizhe; Li, Fuping; Deng, Dong; Chiang, Ying-Chih; Li, Zhenfei; Ren, Ruobing.
Afiliación
  • Han Y; Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • Zhuang Q; State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
  • Sun B; Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201204, China.
  • Lv W; Warshel Institute for Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • Wang S; Tencent AI lab, Shenzhen, Guangdong, 518000, China.
  • Xiao Q; Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, 610041, China.
  • Pang B; Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • Zhou Y; Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • Wang F; Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • Chi P; Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, 610041, China.
  • Wang Q; Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201204, China.
  • Li Z; School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • Zhu L; Warshel Institute for Computational Biology, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • Li F; Human Sperm Bank, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, West China Second Hospital, Sichuan University, Chengdu, 610041, China.
  • Deng D; Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, 610041, China. dengd@scu.edu.cn.
  • Chiang YC; Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China. chiangyc@cuhk.edu.cn.
  • Li Z; State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China. zhenfei.li@sibcb.ac.cn.
  • Ren R; Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China. renruobing@cuhk.edu.cn.
Nat Commun ; 12(1): 449, 2021 01 19.
Article en En | MEDLINE | ID: mdl-33469028
Steroid hormones are essential in stress response, immune system regulation, and reproduction in mammals. Steroids with 3-oxo-Δ4 structure, such as testosterone or progesterone, are catalyzed by steroid 5α-reductases (SRD5As) to generate their corresponding 3-oxo-5α steroids, which are essential for multiple physiological and pathological processes. SRD5A2 is already a target of clinically relevant drugs. However, the detailed mechanism of SRD5A-mediated reduction remains elusive. Here we report the crystal structure of PbSRD5A from Proteobacteria bacterium, a homolog of both SRD5A1 and SRD5A2, in complex with the cofactor NADPH at 2.0 Å resolution. PbSRD5A exists as a monomer comprised of seven transmembrane segments (TMs). The TM1-4 enclose a hydrophobic substrate binding cavity, whereas TM5-7 coordinate cofactor NADPH through extensive hydrogen bonds network. Homology-based structural models of HsSRD5A1 and -2, together with biochemical characterization, define the substrate binding pocket of SRD5As, explain the properties of disease-related mutants and provide an important framework for further understanding of the mechanism of NADPH mediated steroids 3-oxo-Δ4 reduction. Based on these analyses, the design of therapeutic molecules targeting SRD5As with improved specificity and therapeutic efficacy would be possible.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esteroides / 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa / Proteínas Bacterianas Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esteroides / 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa / Proteínas Bacterianas Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido