Structure and dynamics of the RF-amide QRFP receptor GPR103

Abstract

Pyroglutamylated RF amide peptide (QRFP) is a type of peptide hormone with a C-terminal RF-amide motif. QRFP selectively activates class-A categorized GPCR, GPR103 to exert various physiological functions such as energy metabolism and appetite regulation. Here, we report the cryo-electron microscopy structure of the QRFP-GPR103-Gqcomplex at 3.3 Å resolution. Unlike class-A GPCR, QRFP adopts an extended structure baring no secondary structure, with its N-terminal and C-terminal sides recognized by extracellular and transmembrane domains, respectively, of GPR103. The C-terminal heptapeptide of QRFP penetrates into the orthosteric pocket to act in receptor activation. Particularly, the residues that recognize the RF-amide are highly conserved in the RF-amide receptors. Notably, the unique N-terminal helix-loop-helix of the receptor traps the N-terminal side of QRFP with the pendulum-like motion to guide QRFP into the ligand-binding pocket. This movement, reminiscent of class B1 GPCRs except for orientation and structure of the ligand, is critical for the high affinity binding and receptor specificity of QRFP. Structural comparisons with closely related receptors, including RY-amide peptide-recognizing GPCRs, revealed conserved and diversified peptide recognition mechanisms, providing profound insights into the biological significance of RF-amide peptides. This study not only advances our understanding of GPCR-ligand interactions, but also paves the way for the development of novel therapeutics targeting metabolic and appetite disorders and emergency medical care.

Structural insights into the agonist selectivity and structure-based engineering of the adenosine A3 receptor

“…In detail, around α5 of G i , several residues form hydrogen bonds, represented by the interaction between R108 3.50 and C351 H5.23 (superscript indicates the common Gα numbering [CGN] system(Flock et al, 2015)) (Figure 2F). In the ICL2 of A 3 R, V116 34.51 penetrates into the hydrophobic cavity of G i , which is common in class A GPCRs(Akasaka et al, 2022; Hua et al, 2020; Iwama et al, 2023; Izume et al, 2024; Kato et al, 2019; Nagiri et al, 2021; Okamoto et al, 2021; Oshima et al, 2024; Rasmussen et al, 2011; Sano et al, 2023; Yuan et al, 2021; Zhuang et al, 2022) (Figure 2G). Furthermore, extensive ionic interactions are formed across ICL2.…”

Cryo-EM structure of the bicarbonate receptor GPR30

“…13 . At ICL2, M163 34.51 fits into a hydrophobic pocket composed of the α5-helix, the αN-β2 loop, and the β2-β3 loop of the Gα subunit, as in other GPCR-Gq complexes [26][27][28][29][30] (Figure 5C-H). Above it, L159 3.54 and A162 34.50 form extensive hydrophobic interactions with L235 G.H5.15 , L236 G.H5.…”