Jasuja Ravi, Spencer Daniel, Jayaraj Abhilash, Peng Liming, Krishna Meenakshi, Lawney Brian, Patel Priyank, Jayaram Bhyravabhotla, Thayer Kelly M, Beveridge David L, Bhasin Shalender
Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Function Promoting Therapies, Waltham, MA, USA.
iScience. 2021 Apr 9;24(6):102414. doi: 10.1016/j.isci.2021.102414. eCollection 2021 Jun 25.
Sex-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 (K ∼2 nM). Contrary to the prevalent view, we show that estradiol's binding to SHBG is nonlinear, and the "apparent" K changes 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.
性激素结合球蛋白（SHBG）调节雌二醇的转运和生物利用度。尽管人们认为雌二醇以相同亲和力（K~2 nM）与SHBG二聚体的每个单体结合，但雌二醇与SHBG结合的动力学尚未完全了解。与普遍观点相反，我们发现雌二醇与SHBG的结合是非线性的，并且“表观”K会随雌二醇和SHBG浓度的变化而改变。雌二醇与每个SHBG单体的结合会影响两个单体配体结合口袋中的残基，并不同程度地改变两个单体的构象和能量格局。即使在完全结合状态下，单体在能量或构象上也不相同。雌二醇与SHBG的结合涉及双向的单体间变构，这种变构会改变两个单体在各种能量和构象状态之间的分布。单体间变构提供了一种机制，可在生命过程中随着雌二醇浓度的广泛变化来扩展SHBG的结合范围并调节激素的生物利用度。
