Molecular insights into how SHBG dimerization exerts changes on ligand molecular recognition

Concepción Guadarrama-García, Martiniano Bello, Marvin Soriano-Ursúa

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Sex hormone binding globulin (SHBG) is a homodimeric glycoprotein and is the major carrier protein for sex steroids in plasma, regulating sex hormone availability in most vertebrate groups. Although it was initially thought that human dimeric SHBG bound a single ligand at the homodimer interface, studies demonstrated that dimeric SHBG binds a ligand to each subunit with similar affinity. In fact, the findings from recent experimental studies suggest that ligand binding to the SHBG dimer involves a complex allosteric mechanism involving conformational changes that limit observations of the presence of allosteric regulation. Therefore, we combined structural data with molecular dynamics simulations using Molecular Mechanics Generalized-Born Surface Area (MMGBSA) to dissect the structural and energetic basis for molecular recognition between five ligands whose affinities and binding positions on SHBG are known, i.e., 3β,17α-diol; 3β,17β-diol; DHT; norgestrel (NOG); and estradiol (E2), and monomeric and dimeric SHBG. Protein-ligand complexes, involving dimeric SHBG saturated with two ligands on each subunit, reproduce the experimental affinity tendency and allow the observation that dimerization exerts disparate effects on binding affinity, characteristic of negative cooperativity for E2, DHT, and NOG, whereas 3β-17α-diol and 3β-17β-diol lack allostery.

Original languageEnglish
Article number105502
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume197
DOIs
StatePublished - Mar 2020

Keywords

  • MD simulations
  • MMGBSA
  • SHBG
  • Steroids

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