Histidine7.36(305) in the conserved peptide receptor activation domain of the gonadotropin releasing hormone receptor couples peptide binding and receptor activation

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:402

Article

Mayevu, Nkateko M. I.¹  Choe, Han^2,3  Abagyan, Ruben⁴  Seong, Jae Young⁵  Millar, Robert P.^1,6  Katz, Arieh A.¹  Flanagan, Colleen A.^1,7 

[1] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, Div Med Biochem,Med Res Council Receptor Biol Res, ZA-7925 Cape Town, South Africa

[2] Univ Ulsan, Coll Med, Dept Physiol, Seoul 138736, South Korea

[3] Univ Ulsan, Coll Med, Biomed Inst Technol, Seoul 138736, South Korea

[4] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92039 USA

[5] Korea Univ, Grad Sch Med, Seoul 136705, South Korea

[6] Univ Pretoria, Fac Nat & Agr Sci, Mammal Res Inst, ZA-0002 Pretoria, South Africa

[7] Univ Witwatersrand, Fac Hlth Sci, Sch Physiol, ZA-2050 Johannesburg, South Africa

关键词: G protein-coupled receptor (GPCR);    Peptide hormone;    Hormone receptor;    Receptor structure-function;    Peptide interaction;    GnRH;   

DOI  :  10.1016/j.mce.2015.01.008

来源: Elsevier

【 摘 要 】

Transmembrane helix seven residues of G protein-coupled receptors (GPCRs) couple agonist binding to a conserved receptor activation mechanism. Amino-terminal residues of the GnRH peptide determine agonist activity. We investigated GnRH interactions with the His(7.36(305)) residue of the GnRH receptor, using functional and computational analysis of modified GnRH receptors and peptides. Non-polar His(7.36(305)) substitutions decreased receptor affinity for GnRH four- to forty-fold, whereas GnRH signaling potency was more decreased (similar to 150-fold). Uncharged polar His(7.36(305)) substitutions decreased GnRH potency, but not affinity. [2-Nal(3)]-GnRH retained high affinity at receptors with non-polar His(7.36(305)) substitutions, supporting a role for His(7.36(305)) in recognizing Trp(3) of GnRH. Compared with GnRH, [2-Nal(3)]-GnRH potency was lower at the wild type GnRH receptor, but unchanged or higher at mutant receptors. Results suggest that His(7.36(305)) of the GnRH receptor forms two distinct interactions that determine binding to Trp(3) and couple agonist binding to the conserved transmembrane domain network that activates GPCRs. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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