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Res Sq ; 2020 Jul 15.
Article in English | MEDLINE | ID: covidwho-671941


Human steroid 5α-reductase 2 (SRD5α2) as a critical integral membrane enzyme in steroid metabolism catalyzes testosterone to dihydrotestosterone. Mutations on its gene have been linked to 5α-reductase deficiency and prostate cancer. Finasteride and dutasteride as SRD5α2 inhibitors are widely used anti-androgen drugs for benign prostate hyperplasia, which have recently been indicated in the treatment of COVID-19. The molecular mechanisms underlying enzyme catalysis and inhibition remained elusive for SRD5α2 and other eukaryotic integral membrane steroid reductases due to a lack of structural information. Here, we report a crystal structure of human SRD5α2 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 membrane. Structural analysis together with computational and mutagenesis studies reveals molecular mechanisms for the 5α-reduction of testosterone and the finasteride inhibition involving residues E57 and Y91. Molecular dynamics simulation results indicate high conformational dynamics of the cytosolic region regulating the NADPH/NADP + exchange. Mapping disease-causing mutations of SRD5α2 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 will facilitate drug development.

Ann Transl Med ; 8(12): 747, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-640177


Background: The coronavirus disease 2019 (COVID-19) virus has a high incidence rate and strong infectivity. The diagnosis and evaluation of familial outbreaks requires a collective consideration of epidemiological history, molecular detection methods, chest computed tomography (CT), and clinical symptoms. Methods: A group of family patients with COVID-19 diagnosed in Guizhou, China, in February 2020, was retrospectively analyzed. As of March 1, all patients in the group have been discharged from hospital. This study tracked all patients in the group. We report the epidemiology, radiological characteristics, treatment, and clinical outcomes of these patients. Results: We collected a group of 8 clustered cases (3 men and 5 women) from a family with confirmed COVID-19 infection. In the first admission diagnosis, according to the degree of clinical symptoms, the 8 patients were defined as mild type (4/8) or moderate type (4/8). They were also divided according to the CT findings into early period (1/8), progressive period (3/8), and negative on CT scan (4/8); for the first 4 patients, the corresponding CT image scores were 1, 4, 5, and 5 respectively. In this group of COVID-19 patients, half of the patients showed occult clinical manifestations and negative CT performance. We defined these patients as COVID-19-infected patients, or asymptomatic carriers. Conclusions: The family cluster analysis indicated that COVID-19-infected patients (asymptomatic carriers) and symptomatic COVID-19 patients are distinct but coexistent. This may indicate that the infectivity and virulence of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has decreased. In order to block the transmission pathway of this virus before it spreads, we need to identify the presence of asymptomatic carriers as early as possible.