Open AccessExploring the molecular structures that confer ligand selectivity for galanin type II and III receptors
Author(s) -
Yoo Na Lee,
Arfaxad ReyesAlcaraz,
Seongsik Yun,
Cheol Soon Lee,
Jong Ik Hwang,
Jae Young Seong
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0230872
Subject(s) - galanin , g protein coupled receptor , biology , galanin receptor , receptor , transmembrane domain , in silico , agonist , biochemistry , neuropeptide , gene
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, Phe 103 , Phe 106 , and His 110 in the transmembrane helix 3 (TM3) domain; Val 193 , Phe 194 , and Ser 195 in the TM5 domain; and Leu 273 in the extracellular loop 3 (ECL3) domain of GALR2 provide favorable interactions with the Asn 5 , Ala 7 , Phe 11 , and Pro 13 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.