Deciphering the GPER/GPR30-agonist and antagonists interactions using molecular modeling studies, molecular dynamics,...

Area of Science:

• Molecular biology
• Structural biology
• Computational chemistry

Background:

• The G-protein coupled estrogen receptor 1 (GPER1/GPR30) is a key regulator in breast cancer growth and proliferation.
• The absence of a GPER1 crystal structure necessitates computational approaches to understand its function.

Purpose of the Study:

• To construct a 3D model of GPER1 using molecular modeling.
• To investigate GPER1's molecular recognition properties with known agonists and antagonists via docking studies.
• To elucidate the structural basis for GPER1's ligand-binding diversity.

Main Methods:

• Molecular modeling to build the initial GPER1 structure.
• Molecular dynamics (MD) simulations up to 120 ns for structural refinement.
• Molecular docking studies with various GPER1 ligands (agonists and antagonists).

Main Results:

• Identified the estradiol (E2) binding site and other ligand-accepting cavities within GPER1.
• Revealed key interactions, including π-π, hydrophobic, and hydrogen bonds, governing ligand binding.
• Observed conserved binding motifs for G1 and G15 across MD simulations.
• Identified potential protein activation residues (C107 and E275) based on ligand interactions.

Conclusions:

• GPER1 exhibits significant structural flexibility, enabling it to bind a wide array of ligands.
• Ligand binding poses can vary depending on GPER1's conformational states.
• These findings provide insights into GPER1's role in breast cancer and potential therapeutic strategies.