Structure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride.

Autor: Xiao Q; Department of Biology, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.; Faculty of Health Sciences, University of Macau, 999078, Macau, SAR, China., Wang L; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA., Supekar S; Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, 138671, Singapore., Shen T; Tencent AI Lab, 518000, Shenzhen, Guangdong, China., Liu H; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA., Ye F; Tencent AI Lab, 518000, Shenzhen, Guangdong, China., Huang J; Tencent AI Lab, 518000, Shenzhen, Guangdong, China., Fan H; Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, 138671, Singapore. fanh@bii.a-star.edu.sg., Wei Z; Department of Biology, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China. weizy@sustech.edu.cn., Zhang C; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. chengzh@pitt.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Oct 27; Vol. 11 (1), pp. 5430. Date of Electronic Publication: 2020 Oct 27.
DOI: 10.1038/s41467-020-19249-z
Abstrakt: Human steroid 5α-reductase 2 (SRD5A2) is an integral membrane enzyme in steroid metabolism and catalyzes the reduction of testosterone to dihydrotestosterone. Mutations in the SRD5A2 gene have been linked to 5α-reductase deficiency and prostate cancer. Finasteride and dutasteride, as SRD5A2 inhibitors, are widely used antiandrogen drugs for benign prostate hyperplasia. The molecular mechanisms underlying enzyme catalysis and inhibition for SRD5A2 and other eukaryotic integral membrane steroid reductases remain elusive due to a lack of structural information. Here, we report a crystal structure of human SRD5A2 at 2.8 Å, revealing a unique 7-TM structural topology and an intermediate adduct of finasteride and NADPH as NADP-dihydrofinasteride in a largely enclosed binding cavity inside the transmembrane domain. Structural analysis together with computational and mutagenesis studies reveal the molecular mechanisms of the catalyzed reaction and of finasteride inhibition involving residues E57 and Y91. Molecular dynamics simulation results indicate high conformational dynamics of the cytosolic region that regulate NADPH/NADP + exchange. Mapping disease-causing mutations of SRD5A2 to our structure suggests molecular mechanisms for their pathological effects. Our results offer critical structural insights into the function of integral membrane steroid reductases and may facilitate drug development.
Databáze: MEDLINE
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