Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 402, Issue C, Pages 95-106Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2015.01.008
Keywords
G protein-coupled receptor (GPCR); Peptide hormone; Hormone receptor; Receptor structure-function; Peptide interaction; GnRH
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Funding
- South African Medical Research Council
- National Research Foundation
- Korea-South Africa Collaboration Program [2012K1A3A1A09033014]
- MRC program of the National Research Foundation of Korea [2010-0029522]
- National Research Foundation of Korea [2012K1A3A1A09033014, 2010-0029522] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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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