Peptide ligand recognition by G protein-coupled receptors

Abstract

The past few years have seen spectacular progress in the structure determination of G protein-coupled receptors (GPCRs). We now have structural representatives from classes A, B, C, and F. Within the rhodopsin-like class A, most structures belong to the α group, whereas fewer GPCR structures are available from the β, γ, and δ groups, which include peptide GPCRs such as the receptors for neurotensin (β group), opioids, chemokines (γ group), and protease-activated receptors (δ group). Structural information on peptide GPCRs is restricted to complexes with non-peptidic drug-like antagonists with the exception of the chemokine receptor CXCR4 that has been crystallized in the presence of a cyclic peptide antagonist. Notably, the neurotensin receptor 1 is to date the only peptide GPCR whose structure has been solved in the presence of a peptide agonist. Although limited in number, the current peptide GPCR structures reveal great diversity in shape and electrostatic properties of the ligand binding pockets, features that play key roles in the discrimination of ligands. Here, we review these aspects of peptide GPCRs in view of possible models for peptide agonist binding.

Keywords: GPCR structure; chemokine receptors; neurotensin receptor; opioid receptors; peptide GPCRs; peptide agonist; protease activated receptors.

FIGURE 1

Crystal structures of peptide receptors. Receptors were aligned in PyMol. Ligands are shown as yellow sticks, receptors are shown as cartoons. CXCR4 with the cyclic peptide antagonist CVX15 (PDB code 3OE0), DOR with the morphinan antagonist naltrindole (PDB code 4EJ4), NTSR1 with the peptide agonist NTS_8-13 (PDB code 4GRV), and PAR1 with the antagonist vorapaxar (PDB code 3VW7). For comparison, the α group member β₂-adrenergic receptor with the partial inverse agonist carazolol (PDB code 2RH1) is shown. Red lines indicate the putative depth of peptide ligand binding as discussed in the review; black lines indicate the depth of ligand binding as seen in the respective structures. Residues of PAR1, implicated in tethered ligand binding, are shown as purple sticks.

FIGURE 2

Electrostatic surface properties contribute to discrimination between peptide ligands. View from the extracellular side. The receptor surfaces are colored according to their electrostatic potential (scale bar -4 kTe^-1 to +4 kTe^-1; red, negative; blue, positive; PyMol using APBS tools). NOP (PDP code 4EA3); KOR (PDB code 4DJH); DOR (PDB code 4N6H); MOR (PDB code 4KDL); CXCR4 (PDB code 3OE0); CCR5 (PDB code 4MBS); NTSR1 (PDB code 4GRV); PAR1 (PDB code 3VW7). For orientation, the position of transmembrane helix 1 (TM1) and ECL2 (circle) are indicated in NOP. Examples of peptides for opioid receptors highlight the presence or absence of positive charges.