Abstract
The understanding of G-protein coupled receptors (GPCRs) is undergoing a revolution due to increased information about their signaling and the experimental determination of structures for more than 25 receptors. The availability of at least one receptor structure for each of the GPCR classes, well separated in sequence space, enables an integrated superfamily-wide analysis to identify signatures involving the role of conserved residues, conserved contacts, and downstream signaling in the context of receptor structures. In this study, we align the transmembrane (TM) domains of all experimental GPCR structures to maximize the conserved inter-helical contacts. The resulting superfamily-wide GpcR Sequence-Structure (GRoSS) alignment of the TM domains for all human GPCR sequences is sufficient to generate a phylogenetic tree that correctly distinguishes all different GPCR classes, suggesting that the class-level differences in the GPCR superfamily are encoded at least partly in the TM domains. The inter-helical contacts conserved across all GPCR classes describe the evolutionarily conserved GPCR structural fold. The corresponding structural alignment of the inactive and active conformations, available for a few GPCRs, identifies activation hot-spot residues in the TM domains that get rewired upon activation. Many GPCR mutations, known to alter receptor signaling and cause disease, are located at these conserved contact and activation hot-spot residue positions. The GRoSS alignment places the chemosensory receptor subfamilies for bitter taste (TAS2R) and pheromones (Vomeronasal, VN1R) in the rhodopsin family, known to contain the chemosensory olfactory receptor subfamily. The GRoSS alignment also enables the quantification of the structural variability in the TM regions of experimental structures, useful for homology modeling and structure prediction of receptors. Furthermore, this alignment identifies structurally and functionally important residues in all human GPCRs. These residues can be used to make testable hypotheses about the structural basis of receptor function and about the molecular basis of disease-associated single nucleotide polymorphisms.
Highlights
Structural revolution in the G-protein coupled receptors (GPCRs) superfamilyGprotein-coupled receptors (GPCRs) comprise the largest superfamily of integral membrane proteins, covering *3% of the human proteome
We extended the list of human GPCRs of Fredriksson et al [34], with the proteins considered by the GPCR Network [5] and by International Union of Basic and Clinical Pharmacology (IUPHAR) [36]
For several cases in class A, we find TM alignments that have a lower root mean squared deviation (RMSD) than the alignment that conserves the correspondence of the same Ballesteros-Weinstein (BW) residue positions [12]
Summary
Gprotein-coupled receptors (GPCRs) comprise the largest superfamily of integral membrane proteins, covering *3% of the human proteome They mediate transmembrane (TM) signal transduction by allosterically facilitating information transfer across the cellular membrane in response to extracellular signals [1, 2]. The GPCRs are pleiotropic proteins responsible for sensing a diverse set of extracellular signals ranging from photons and small molecules (neurotransmitters, metabolites, odorants, tastants) to large oligopeptides (chemokines, incretins), and converting them into one or more intracellular signaling cascades. Rhodopsin has been recently crystallized with arrestin [8] providing the first detailed snapshot of the receptor before and during internalization These new structures inspire a full spectrum of mechanistic studies into the GPCR biology, and will guide the functional understanding and pharmacological targeting of these receptors [9,10,11]
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