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

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Dynamics

Background:

• Sex hormone binding globulin (SHBG) is a key plasma glycoprotein regulating sex steroid availability.
• SHBG exists as a homodimer, and its ligand-binding mechanisms have been debated.
• Recent studies suggest complex allosteric regulation in SHBG ligand binding.

Purpose of the Study:

• To investigate the structural and energetic basis of ligand recognition by monomeric and dimeric SHBG.
• To dissect the allosteric mechanisms governing sex hormone binding to SHBG.
• To compare binding affinities and allosteric effects for five known SHBG ligands.

Main Methods:

• Combined structural data with molecular dynamics simulations.
• Utilized Molecular Mechanics Generalized-Born Surface Area (MMGBSA) calculations.
• Analyzed protein-ligand complexes of monomeric and dimeric SHBG with five ligands (3β,17α-diol, 3β,17β-diol, DHT, norgestrel, estradiol).

Main Results:

• Simulations of saturated dimeric SHBG reproduced experimental affinity trends.
• Dimerization significantly impacted binding affinities, indicating negative cooperativity for estradiol, DHT, and norgestrel.
• 3β-17α-diol and 3β-17β-diol binding to dimeric SHBG lacked observable allosteric effects.

Conclusions:

• SHBG dimerization modulates sex steroid binding affinity through complex allosteric mechanisms.
• Negative cooperativity was identified for specific ligands, influencing hormone availability.
• The study provides structural and energetic insights into SHBG's role in sex hormone regulation.