FSHR activation through small molecule modulators: Mechanistic insights from MD simulations

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• The follicle-stimulating hormone receptor (FSHR) is crucial for reproduction, cancer, and osteoporosis.
• Small molecule FSHR modulators are vital therapeutic targets, identified via high-throughput screening and in vitro assays.
• The precise binding sites and structural impacts of these modulators remain largely unknown.

Purpose of the Study:

• To elucidate the binding interactions and conformational changes associated with FSHR modulators.
• To compare structural dynamics between agonist/FSH-bound and antagonist-bound FSHR.
• To identify conserved mechanisms for potential drug design.

Main Methods:

• Molecular docking simulations were employed to analyze FSHR modulators.
• Molecular Dynamics (MD) simulations were used to compare domain motions.
• FSHR structures bound to agonists and antagonists were analyzed.

Main Results:

• Agonist and antagonist modulators bind to the same site but engage different residues within the transmembrane domain (TMD).
• Specific residues (Ile522, Ala595, Ile602, Val604) in FSHR(TMD) interact exclusively with agonists and are conserved in LHCGR.
• Agonist binding induced significant conformational changes in TM helices 3, 4, and 6, a pattern observed in related GPCRs.

Conclusions:

• Distinct interactions and conformational changes driven by agonist binding at the FSHR TMD provide a basis for understanding FSHR modulation.
• Conserved activation mechanisms across G protein-coupled receptors (GPCRs) suggest potential for designing novel, targeted modulators.