The Structural Basis of Peptide Binding at Class A G Protein-Coupled Receptors

Abstract

G protein-coupled receptors (GPCRs) represent the largest membrane protein family and a significant target class for therapeutics. Receptors from GPCRs’ largest class, class A, influence virtually every aspect of human physiology. About 45% of the members of this family endogenously bind flexible peptides or peptides segments within larger protein ligands. While many of these peptides have been structurally characterized in their solution state, the few studies of peptides in their receptor-bound state suggest that these peptides interact with a shared set of residues and undergo significant conformational changes. For the purpose of understanding binding dynamics and the development of peptidomimetic drug compounds, further studies should investigate the peptide ligands that are complexed to their cognate receptor.

AI protein structure prediction-based modeling and mutagenesis of a protostome receptor and peptide ligands reveal key residues for their interaction

“…S8–S11 ). This model had conserved bound conformations in extracellular loops 1 and 2 among peptide GPCRs, with extracellular loop 2 forming a β hairpin ( 15 ) ( Fig. S7 C ).…”

“…To examine the relevance of our work to other amidated peptide receptors, we also compared our findings with previous receptor comparison studies ( 13 , 15 ) (See Supporting Results and Discussion and Table S7 ). Our results are consistent with a bound orientation of ALK peptides in which both the N- and C-termini of the peptide ligand are within the putative-binding pocket of the receptor, with the N-terminus pointing deep in the pocket.…”

“…Although a growing number of neuropeptides and their receptors have been characterized (6)(7)(8)(9)(10)(11), molecular-level details of how peptide ligands engage their receptors remain poorly understood in many cases. Ideally, this information is obtained through high-resolution structures of a GPCR in a bound state with its peptide ligand (e.g., by X-ray crystallography, NMR, or cryogenic electron microscopy) (12)(13)(14)(15). However, obtaining high-resolution structures remains a daunting task for most GPCRs, particularly for neuropeptide signaling systems that are only present in protostomes (most invertebrates) that lack wellstudied homologs (12,13,15).…”

“…Ideally, this information is obtained through high-resolution structures of a GPCR in a bound state with its peptide ligand (e.g., by X-ray crystallography, NMR, or cryogenic electron microscopy) (12)(13)(14)(15). However, obtaining high-resolution structures remains a daunting task for most GPCRs, particularly for neuropeptide signaling systems that are only present in protostomes (most invertebrates) that lack wellstudied homologs (12,13,15). Thus, previous work has often used amino acid substitution and other experiments to characterize the roles of specific residues in a ligand that may be critical for receptor activity (10).…”

“…Ideally, this information is obtained through high-resolution structures of a GPCR in a bound state with its peptide ligand ( e.g. , by X-ray crystallography, NMR, or cryogenic-EM) ( 12 , 13 , 14 , 15 ). However, obtaining high-resolution structures remains a daunting task for most GPCRs, particularly for neuropeptide signaling systems that are only present in protostomes (most invertebrates) that lack well-studied homologs ( 12 , 13 , 15 ).…”