What Makes GPCRs from Different Families Bind to the Same Ligand?
Kwabena Owusu Dankwah1, Jonathon E Mohl1,2,3,4, Khodeza Begum2,4
1Computational Science Program, The University of Texas at El Paso, El Paso, TX 79968, USA.
Biomolecules
|July 27, 2022
Summary
Computational analysis reveals that similar binding pockets in G protein-coupled receptors (GPCRs) predict similar ligand interactions and affinities. This discovery aids in accelerating drug discovery and repurposing efforts.
Area of Science:
- Structural Biology
- Computational Chemistry
- Pharmacology
Background:
- G protein-coupled receptors (GPCRs) are crucial cell-surface proteins involved in signal transduction and are major drug targets.
- Advancements in 3D structural data for GPCRs and their ligands enable computational prediction of ligand binding.
- Computational approaches offer a viable alternative to experimental methods in early-stage ligand discovery.
Purpose of the Study:
- To computationally investigate the binding of a single ligand across diverse GPCR families.
- To understand the relationship between local 3D structural similarities in GPCRs and their ligand binding pockets.
- To explore how pocket similarity influences ligand-receptor interactions and binding affinity.
Main Methods:
- Utilized 3D structural comparisons of GPCRs that bind to the same ligand.
- Analyzed local structural similarities, often overlapping with binding pocket regions.
- Employed APoc for assessing pocket similarity based on backbone geometry and side-chain orientation.
- Correlated pocket structural similarity with electrostatic properties.
Main Results:
- Identified local 3D structural similarities in GPCRs binding the same ligand, frequently coinciding with binding pockets.
- Found significant similarity in binding pockets based on geometry and side-chain orientation.
- Demonstrated a positive correlation between pocket similarity and electrostatic properties.
- Established that greater pocket similarity leads to more consistent ligand-residue interactions, conformations, and binding affinities.
Conclusions:
- Local 3D structural similarities in GPCRs are indicative of conserved binding pocket characteristics.
- Binding pocket similarity is a strong predictor of ligand interaction patterns and binding affinity across different GPCRs.
- These findings can enhance protein function prediction, drug repurposing, and toxicity assessment, thereby accelerating drug development.
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