Glu^2.53(90) of the GnRH receptor is part of the conserved G protein-coupled receptor structure and does not form a salt-bridge with Lys^3.32(121).

GnRH receptor mutations, Glu^2.53(90)Lys and Glu^2.53(90)Asp, cause congenital hypogonadotropic hypogonadism. The Glu^2.53(90) side-chain has been proposed to form an intramolecular salt-bridge with Lys^3.32(121), but conserved intramolecular interaction networks in G protein-coupled receptor crystal structures predict that it interacts with Ser^3.35(124) and Trp^6.48(280). We investigated interhelical interactions of Glu^2.53(90) that stabilise GnRH receptor folding using functional analyses and computational modelling of mutant receptors. The Glu^2.53(90)Asp mutant was non-functional, but mutants with hydrophobic amino acids or Arg substituted for Glu^2.53(90) were functional, excluding a salt-bridge interaction. The Glu^2.53(90)Arg and Trp^6.48(280)Arg mutants had decreased affinity for GnRH. Models showed that congenital Glu^2.53(90)Lys and Glu^2.53(90)Asp mutations disrupt interactions with Ser^3.35(124) and Trp^6.48(280) respectively, whereas the Glu^2.53(90)Arg and Trp^6.48(280)Arg mutations preserve intramolecular contacts, but increase distance between the transmembrane helices. Our results show that disruption of interhelical contacts that are conserved in G protein-coupled receptors accounts for the effects of some disease-associated GnRH receptor mutations.

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