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

TY - JOUR

T1 - Molecular mechanism of Zn2+ agonism in the extracellular domain of GPR39

AU - Storjohann, Laura

AU - Holst, Birgitte

AU - Schwartz, Thue W

N1 - 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

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1016/j.febslet.2008.06.030

DO - 10.1016/j.febslet.2008.06.030

M3 - Journal article

C2 - 18588883

SN - 0014-5793

VL - 582

SP - 2583

EP - 2588

JO - FEBS Letters

JF - FEBS Letters

IS - 17

ER -