GPCRana

GPCRana quantifies residue-residue contact scores (RRCS) to compare conformational states of class A G-protein-coupled receptors (GPCRs) and identify common activation pathways.

Key Features:

• Quantitative Analysis of GPCR Structures: Quantifies conformational changes across class A GPCRs using a dataset comprising 234 structures from 45 different receptors.
• Comparison of Residue-Residue Contact Scores (RRCS): Compares RRCS between two GPCR structures to reveal structural variations and their functional implications.
• Activation Pathway Analysis: Identifies a common activation pathway in class A GPCRs involving 34 residue pairs and 35 residues and integrating motifs CWxP, DRY, Na+ pocket, NPxxY, and PIF to link the ligand-binding pocket to the G-protein coupling region.
• Ligand-Receptor Interaction Analysis: Examines residue-level ligand-receptor interactions and their effects on receptor activation, including the outward movement of transmembrane helix 6 (TM6).
• Mechanistic Insights into Activation and Mutations: Provides mechanistic interpretation of constitutively activating, inactivating, and disease-related mutations by analyzing residue contributions to receptor activation.

Scientific Applications:

• Drug Discovery and Development: Elucidates activation pathways and key residue interactions to aid identification of therapeutic targets within GPCRs.
• Structural Biology Research: Enables exploration of GPCR structural dynamics and allosteric activation mechanisms.
• Mutagenesis Studies: Supports design and interpretation of site-directed mutagenesis experiments by predicting how mutations in specific residues affect receptor activity.

Methodology:

GPCRana quantifies conformational changes by comparing residue-residue contact scores (RRCS) across GPCR structures and integrates these comparisons from extensive structural analyses to derive a unified activation mechanism.