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

Abstract

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.

Effects on Steroid 5-Alpha Reductase Gene Expression of Thai Rice Bran Extracts and Molecular Dynamics Study on SRD5A2

“…It is obvious that finasteride was more likely to interact with NADPH via VDW and pi -alkyl interaction. Nevertheless, a covalent bond has been suggested to connect the nicotinamide C-4 atom of NADPH and the C-2 atom at the pyridone ring of finasteride and then create an intermediate adduct between NADPH and finasteride (NADP–dihydrofinasteride) [ 34 , 91 ]. In addition, the key residues in the SRD5A2 binding cavity, such as Ser31, Gly32, Trp53, Glu57, Try91, and Arg94, were prone to form interactions with finasteride.…”

“…Loop 1 (L1) has been suggested to be a gate domain that controls the NADPH/NADP + exchange from the cytosol. A previous study reported that SRD5A2 catalyses the hydride transfer from NADPH to finasteride, resulting in the formation of a stable intermediate adduct, namely NADP–dihydrofinasteride (NADP–DHF), via a covalent bond [ 34 ]. Consequently, SRD5A2 is inhibited irreversibly.…”

“…Consequently, SRD5A2 is inhibited irreversibly. The key residues E57 (Glu57), R114 (Arg114), and F118 (Phe118) inside the SRD5A2 pocket have been suggested to interact with the intermediate adduct of finasteride and steroid substrate [ 34 ].…”

“…The crystal structure of human SRD5A2 in complex with NADPH and finasteride was retrieved from the Protein Data Bank (PDB) with the PDB ID 7BW1 [ 34 ]. SRD5A2 was prepared in Discovery Studio version 2.5 software.…”

Physicochemical Characterization of Finasteride Nanosystem for Enhanced Topical Delivery

“… 6 FNS is a highly lipophilic compound 7 and an analog of androgen steroidal hormones like testosterone and dihydrotestosterone. 8 , 9 The FNS exerts its action by inhibiting type II 5α reductase enzyme. 10 The adverse events reported with oral intake of FNS are sexual disorders such as impotency, ejaculation disorder, erectile dysfunction and mental impairment.…”