G-protein-coupled receptors (GPCRs) are the largest family of human
membrane proteins and represent the primary targets of about one third
of currently marketed drugs. Despite the critical importance,
experimental structures have been determined for only a limited portion
of GPCRs and functional mechanisms of GPCRs remain poorly understood.
Here, we have constructed novel sequence coevolutionary models of the A
and B classes of GPCRs and compared them with residue contact frequency
maps generated with available experimental structures. Significant
portions of structural residue contacts were successfully detected in
the sequence-based covariational models. “Exception” residue contacts
predicted from sequence coevolutionary models but not available
structures added missing links that were important for GPCR activation
and allosteric modulation. Moreover, we identified distinct residue
contacts involving different sets of functional motifs for GPCR
activation, such as the Na+ pocket, CWxP, DRY, PIF and NPxxY motifs in
the class A and the HETx and PxxG motifs in the class B. Finally, we
systematically uncovered critical residue contacts tuned by allosteric
modulation in the two classes of GPCRs, including those from the
activation motifs and particularly the extracellular and intracellular
loops in class A GPCRs. These findings provide a promising framework for
rational design of ligands to regulate GPCR activation and allosteric
modulation.
Allosteric Modulation and Thermodynamic Constraints in Occupancy Models of Oligomeric G Protein-Coupled Receptors
