Diversity and modularity of G protein-coupled receptor structures

Abstract

G protein-coupled receptors (GPCRs) comprise the most “prolific” family of cell membrane proteins, which share a common mechanism of signal transduction, but greatly vary in ligand recognition and function. Crystal structures are now available for rhodopsin, adrenergic, and adenosine receptors in both inactive and activated forms, as well as for chemokine, dopamine, and histamine receptors in inactive conformations. Here we review common structural features, outline the scope of structural diversity of GPCRs at different levels of homology and briefly discuss impact of the structures on drug discovery. Given the current set of GPCR crystal structures, a distinct modularity is now being observed between the extracellular (ligand-binding) and intracellular (signaling) regions. The rapidly expanding repertoire of GPCR structures provides a solid framework for experimental and molecular modeling studies, and helps to chart a roadmap for comprehensive structural coverage of the whole superfamily and an understanding of GPCR biological and therapeutic mechanisms.

Structural dynamics and energetics underlying allosteric inactivation of the cannabinoid receptor CB 1

“…5, blue circle) and H8 (site 404) (Fig. 5, orange circle) as well as previous biophysical and crystallographic studies of other GPCRs (10,39). The model shows no changes in the antagonist bound state (R) (Fig.…”

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

“…The extracellular region (comprising the N terminus of the protein) is characterized by a high structural diversity allowing the recognition of a wide spectrum of ligands. Interhelical bonds and hydrophobic interactions between highly conserved residues in GPCR provide the stability of the TM region (Palczewski et al, 2000;Katritch et al, 2012), which also harbors a number of kinks elicited by Pro residues, segregating the receptor into ligand binding and receptor signaling 'modules' (Latek et al, 2012). As shown by crystallographic studies, the overall structure of GPCR proteins is highly conserved, but significant diversities can be observed in the loop regions and in the pitch and orientation of individual TM in the helical bundle (Lu and Wu, 2016).…”

Michael Acceptor Approach to the Design of New Salvinorin A- Based High Affinity Ligands to the Kappa-Opioid Receptor

“…Although technically in an inactive state, it has been shown that large-scale movements of amino acid residues in the orthosteric binding site of class A GPCRs are not requisite for activation of the receptor [26]. In addition, it has been found that virtual screening for ligands using inactive-state GPCRs can produces agonist leads (see for example Negri et al) [27].…”