Molecular architecture of G protein-coupled receptors

Abstract

This review of the current literature on mutations in G protein-coupled receptors (GPCRs) of the rhodopsin-related family intends to draw inferences from amino acid sequences for single receptors and multiple sequence alignments with regard to the molecular architecture of this class of receptors. For this purpose a comprehensive list of mutations within the transmembrane helical regions (TMs; over 390 mutations from 38 different receptor subtypes) and their effects on function was compiled, and an alignment of known GPCR sequences (over 150 separate sequences) was made. Regions most prominently involved in ligand binding are located in TMs 3, 5, 6, and 7. Position 3.32 in TM3 is occupied by a D in all biogenic amine receptors (sequence conservation) but may be occupied by uncharged residues in other receptors while its role in ligand binding is analogous (function conservation). TMs 5, 6, and 7 display considerable sequence conservation throughout the majority of GPCRs investigated, but not necessarily at those positions involved in ligand binding. However, considerable function conservation is observed for positions 5.42 (frequently hydrophilic), 5.46 (small amino acids required for agonist binding to "small ligand" receptors), 6.52 and 7.39 (high variability), and 7.43 (frequently aromatic). A general conclusion of this review is that there is overwhelming conservation of structure-function correlates among GPCRs. Thus, it is now possible to cross-correlate the results of mutagenesis studies between GPCRs of different subfamilies, and to use those results to predict the function of specific residues in new GPCR sequences.

The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor

“…Furthermore, the detrimental effect of the simultaneous presence of Asp at both the 2.50 and 7.49 loci on receptor expression is not observed in most other GPCRs studied (9,10,12,17,31 (9,10,12,14). Only the -opioid receptor is similar to the GnRH receptor in manifesting complete loss of binding with Asp present at both the H2 and H7 loci (11).…”

“…The amino acid side chains in the H2/H7 microdomain of the GnRH receptor that are required for efficient coupling to heterotrimeric G proteins differ from those required in other GPCRs. In GPCRs which have the canonical wild-type Asp-Asn arrangement of the microdomain, the Asp 2.50 side chain is required for efficient G protein coupling (9,10,12,14,31). In addition, a polar residue is required in H7.…”

“…This suggests that mutant GPCRs that do not have an Asp residue in the H2/H7 microdomain are able to assume an activated conformation, but that this conformation is different from the activated conformation of the wild-type receptors that have an Asp residue in this microdomain. Mutation of the Asp 2.50 side chain has variable effects on signal transduction in different receptors (9,31). Mutating the Asp 2.50 residue of the ␣ 2 -adrenergic receptor had differential effects on different signal transduction pathways.…”

Evidence for the recognition of non‐nucleotide antagonists within the transmembrane domains of the human P2Y1 receptor

“…In the absence of physically determined 3D structures for the rhodopsin-like GPCRs, numerous ligand binding sites, including those for biogenic amines and adenosine within the transmembrane helical domains (TMs), have been probed extensively using site-directed mutagenesis [van Rhee and Jacobson, 1996]. Agonist action at both P2Y 1 [Jiang et al, 1997;Moro et al, 1998] and P2Y 2 receptors [Erb et al, 1995] is dependent on specific residues within TMs 3, 5, 6, or 7.…”

Docking of Linear Peptide Antagonists into the Human V1a Vasopressin Receptor

“…Extensive mutational analysis and receptor three-dimensional molecular modeling have led to valuable information concerning "small ligand" and peptide/protein ligand receptor-binding sites (for review, see Refs. [1][2][3][4][5][6].…”