Abstract
Galanin receptors (GALRs) belong to the superfamily of G-protein coupled receptors. The three GALR subtypes (GALR1, GALR2, and GALR3) are activated by their endogenous ligands: spexin (SPX) and galanin (GAL). The synthetic SPX-based GALR2-specific agonist, SG2A, plays a dual role in the regulation of appetite and depression-like behaviors. Little is known, however, about the molecular interaction between GALR2 and SG2A. Using site-directed mutagenesis and domain swapping between GALR2 and GALR3, we identified residues in GALR2 that promote interaction with SG2A and residues in GALR3 that inhibit interaction with SG2A. In particular, Phe103, Phe106, and His110 in the transmembrane helix 3 (TM3) domain; Val193, Phe194, and Ser195 in the TM5 domain; and Leu273 in the extracellular loop 3 (ECL3) domain of GALR2 provide favorable interactions with the Asn5, Ala7, Phe11, and Pro13 residues of SG2A. Our results explain how SG2A achieves selective interaction with GALR2 and inhibits interaction with GALR3. The results described here can be used broadly for in silico virtual screening of small molecules for the development of GALR subtype-specific agonists and/or antagonists.
Highlights
G-protein-coupled receptors (GPCRs) are a superfamily of membrane proteins with more than 860 members in humans [1]
The GALR2/3 chimeric receptors had the N-terminal domain of GALR2 and the C-terminal domain of GALR3, whereas the GALR3/2 chimeric receptors had the N-terminal domain of GALR3 and the C-terminal domain of GALR2 (Fig 2)
The GALR2/3 chimeric receptors did not respond to the Qu-SPX peptide; except for GALR2/3f, they did respond to SPX
Summary
G-protein-coupled receptors (GPCRs) are a superfamily of membrane proteins with more than 860 members in humans [1]. GPCRs are responsible for a variety of physiological functions including growth, homeostasis, reproduction, sleep, appetite, mood behavior, and others. Because of their diverse roles, GPCRs represent the largest family of therapeutic targets in human medicine [2, 3]. GPCRs are modulated by various endogenous ligands including peptides, amino acids, lipids, and nucleotides [4,5,6,7,8]. The characterization of crystal structures of agonist/antagonist-bound GPCRs provides crucial clues for the development of synthetic agonists and antagonists [9, 10]. Site-directed mutagenesis [11,12,13] has yielded
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