6pyb | pdb_00006pyb
Sex Hormone-binding globulin mutant E176K in complex with DVT
Structural highlights
Publication Abstract from PubMedSex hormone-binding globulin (SHBG) determines the equilibrium between free and protein-bound androgens and estrogens in the blood and regulates their access to target tissues. Using crystallographic approaches and radiolabeled competitive binding-capacity assays, we report here how two non-steroidal compounds bind to human SHBG, and how they influence androgen activity in cell culture. We found that one of these compounds, (-)3,4-divanillyltetrahydrofuran (DVT), present in stinging nettle root extracts and used as a nutraceutical, binds SHBG with relatively low affinity. By contrast a, synthetic compound, 3-(1H-imidazol-1-ylmethyl)-2phenyl-1H-indole (IPI), bound SHBG with an affinity similar to that of testosterone and estradiol. Crystal structures of SHBG in complex with DVT or IPI at 1.71-1.80 A resolutions revealed their unique orientations in the SHBG ligand-binding pocket and suggested opportunities for the design of other non-steroidal ligands of SHBG. As observed for estradiol but not testosterone, IPI binding to SHBG was reduced by ~20 fold in the presence of zinc, whereas DVT binding was almost completely lost. Estradiol dependent fibulin-2 interactions with SHBG similarly occurred for IPI-bound SHBG, but not with DVT-bound SHBG. Both DVT and IPI increased the activity of testosterone in a cell culture androgen reporter system by competitively displacing testosterone from SHBG. These findings indicate how non-steroidal ligands of SHBG maybe designed to modulate the bioavailability of sex steroids. Molecular interactions between sex hormone-binding globulin and non-steroidal ligands that enhance androgen action.,Round P, Das S, Wu TS, Wahala K, Van Petegem F, Hammond GL J Biol Chem. 2019 Dec 18. pii: RA119.011051. doi: 10.1074/jbc.RA119.011051. PMID:31852737[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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