Molecular mechanism of Zn2+ agonism in the extracellular domain of GPR39

Research output: Contribution to journalJournal articleResearchpeer-review

Laura Storjohann, Birgitte Holst, Thue W Schwartz

Ala substitution of potential metal-ion binding residues in the main ligand-binding pocket of the Zn2+-activated G protein-coupled receptor 39 (GPR39) receptor did not decrease Zn2+ potency. In contrast, Zn2+ stimulation was eliminated by combined substitution of His17 and His19, located in the N-terminal segment. Surprisingly, substitution of Asp313 located in extracellular loop 3 greatly increased ligand-independent signaling and apparently eliminated Zn2+-induced activation. It is proposed that Zn2+ acts as an agonist for GPR39, not in the classical manner by directly stabilizing an active conformation of the transmembrane domain, but instead by binding to His17 and His19 in the extracellular domain and potentially by diverting Asp313 from functioning as a tethered inverse agonist through engaging this residue in a tridentate metal-ion binding site.
Original languageEnglish
JournalFEBS Letters
Volume582
Issue number17
Pages (from-to)2583-8
Number of pages5
ISSN0014-5793
DOIs
Publication statusPublished - 2008

Bibliographical note

Keywords: Alanine; Amino Acid Substitution; Animals; Aspartic Acid; Binding Sites; Cations, Divalent; Cell Line; Histidine; Humans; Mice; Protein Structure, Tertiary; Rats; Receptors, G-Protein-Coupled; Zinc

ID: 10149924