摘要：SummarySex-hormone-binding globulin (SHBG) regulates the transport and bioavailability of estradiol. The dynamics of estradiol's binding to SHBG are incompletely understood, although it is believed that estradiol binds to each monomer of SHBG dimer with identical affinity (Kd∼2 nM). Contrary to the prevalent view, we show that estradiol's binding to SHBG is nonlinear, and the "apparent" Kdchanges with varying estradiol and SHBG concentrations. Estradiol's binding to each SHBG monomer influences residues in the ligand-binding pocket of both monomers and differentially alters the conformational and energy landscapes of both monomers. Monomers are not energetically or conformationally equivalent even in fully bound state.Estradiol's binding to SHBG involves bidirectional, inter-monomeric allostery that changes the distribution of both monomers among various energy and conformational states. Inter-monomeric allostery offers a mechanism to extend the binding range of SHBG and regulate hormone bioavailability as estradiol concentrations vary widely during life.Highlights•SHBG monomers exhibit conformational heterogeneity in free as well as bound states and are conformationally coupled•Estradiol’s binding to SHBG is nonlinear and the “apparent”Kdchanges with varying estradiol and SHBG concentrations•Estradiol’s binding to each SHBG monomer differentially alters the conformational and energy landscapes of both monomers•Inter-monomeric allostery offers a versatile mechanism to extend the binding range of SHBG and regulate hormone bioavailabilityGraphical abstractDisplay OmittedBiochemistry; Endocrinology
