6PYF

Sex Hormone-binding globulin mutant E176K in complex with Estradiol

Summary for 6PYF

• Entry DOI: 10.2210/pdb6pyf/pdb
• Descriptor: Sex hormone-binding globulin, CALCIUM ION, ESTRADIOL, ... (4 entities in total)
• Functional Keywords: sex steroid, transport, binding globulin, hormone
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 22923.15

Authors

Round, P.W.,Wu, T.S.,Das, S.,Van Petegem, F. (deposition date: 2019-07-29, release date: 2019-12-25, Last modification date: 2024-10-16)

Primary citation

Round, P.,Das, S.,Wu, T.S.,Wahala, K.,Van Petegem, F.,Hammond, G.L.
Molecular interactions between sex hormone-binding globulin and nonsteroidal ligands that enhance androgen activity.
J.Biol.Chem., 295:1202-1211, 2020

PubMed Abstract: Sex 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 nonsteroidal 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 Å resolutions revealed their unique orientations in the SHBG ligand-binding pocket and suggested opportunities for the design of other nonsteroidal 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 nonsteroidal ligands of SHBG maybe designed to modulate the bioavailability of sex steroids.

PubMed: 31852737
DOI: 10.1074/jbc.RA119.011051

Experimental method

X-RAY DIFFRACTION (1.73 Å)