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Published on: June 9, 2017
Understanding the molecular basis of agonist/antagonist mechanism of GPER1/GPR30 through structural and energetic
David Méndez-Luna1, Martiniano Bello1, José Correa-Basurto1
1Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, Mexico City CP 11340, Mexico.
Abstract:
The G-protein coupled receptors (GPCRs) represent the largest superfamily of membrane proteins in charge to pass the cell signaling after binding with their cognate ligands to the cell interior. In breast cancer, a GPCR named GPER1 plays a key role in the process of growth and the proliferation of cancer cells. In a previous study, theoretical methods were applied to construct a model of GPER1, which later was submitted to molecular dynamics (MD) simulations to perform a docking calculation. Based on this preceding work, it is known that GPER1 is sensitive to structural differences in its binding site. However, due to the nature of that past study, conformational changes linked to the ligand binding were not observed. Therefore, in this study, in order to explore the conformational changes coupled to the agonist/antagonist binding, MD simulations of about 0.25μs were performed for the free and bound states, summarizing 0.75μs of MD simulation in total. For the bound states, one agonist (G-1) and antagonist (G-15) were chosen since is widely known that these two molecules cause an impact on GPER1 mobility. Based on the conformational ensemble generated through MD simulations, we found that despite G-1 and G-15 being stabilized by similar map of residues, the structural differences between both ligands impact the hydrogen bond pattern not only at the GPER1 binding site but also along the seven-helix bundle, causing significant differences in the conformational mobility along the extracellular and cytoplasmic domain, and to a lesser degree in the curvatures of helix 2, helix 3 and helix 7 between the free and bound states, which is in agreement with reported literature, and might be linked to microscopic characteristics of the activated-inactivated transition. Furthermore, binding free energy calculations using the MM/GBSA method for the bound states, followed by an alanine scanning analysis allowed us to identify some important residues for the complex stabilization.
Insights
This study reveals how GPER1 receptor structural changes are influenced by agonist (G-1) and antagonist (G-15) binding, impacting breast cancer cell signaling and providing insights into receptor activation mechanisms.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- G-protein coupled receptors (GPCRs) are crucial for cell signaling.
- GPER1, a GPCR, is implicated in breast cancer growth and proliferation.
- Previous studies modeled GPER1 and noted its sensitivity to binding site variations.
Purpose of the Study:
- To investigate conformational changes in GPER1 upon agonist (G-1) and antagonist (G-15) binding.
- To understand how ligand binding affects GPER1 mobility and structural dynamics.
- To identify key residues involved in GPER1-ligand complex stabilization.
Main Methods:
- Extended molecular dynamics (MD) simulations (0.75 μs total) for free and ligand-bound GPER1 states.
- Analysis of hydrogen bond patterns and conformational mobility across the receptor.
- Binding free energy calculations (MM/GBSA) and alanine scanning for residue analysis.
Main Results:
- Ligand binding (G-1, G-15) alters GPER1 hydrogen bond patterns and conformational mobility.
- Significant differences observed in extracellular and cytoplasmic domains, and helix curvatures.
- Key residues contributing to GPER1-ligand complex stability were identified.
Conclusions:
- Ligand-induced structural changes in GPER1 are linked to its activation/inactivation transition.
- Understanding these dynamics is vital for developing targeted breast cancer therapies.
- The study provides a detailed molecular perspective on GPER1-ligand interactions.
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