TY - JOUR
T1 - Ligand binding and activation of the secretin receptor, a prototypic family B G protein-coupled receptor
AU - Miller, Laurence J.
AU - Dong, Maoqing
AU - Harikumar, Kaleeckal G.
PY - 2012/5
Y1 - 2012/5
N2 - The secretin receptor is a prototypic member of family B G protein-coupled receptors that binds and responds to a linear 27-residue peptide natural ligand. The carboxyl-terminal region of this peptide assumes a helical conformation that occupies the peptide-binding cleft within the structurally complex disulphide-bonded amino-terminal domain of this receptor. The amino terminus of secretin is directed toward the core helical bundle domain of this receptor that seems to be structurally distinct from the analogous region of family A G protein-coupled receptors. This amino-terminal region of secretin is critical for its biological activity, to stimulate Gs coupling and the agonist-induced cAMP response. While the natural peptide ligand is known to span the two key receptor domains, with multiple residue-residue approximation constraints well established, the orientation of the receptor amino terminus relative to the receptor core helical bundle domain is still unclear. Fluorescence studies have established that the mid-region and carboxyl-terminal end of secretin are protected by the receptor peptide-binding cleft and the amino terminus of secretin is most exposed to the aqueous milieu as it is directed toward the receptor core, with the mid-region of the peptide becoming more exposed upon receptor activation. Like other family B peptide hormone receptors, the secretin receptor is constitutively present in a structurally specific homo-dimeric complex built around the lipid-exposed face of transmembrane segment four. This complex is important for facilitating G protein association and achieving the high affinity state of this receptor.
AB - The secretin receptor is a prototypic member of family B G protein-coupled receptors that binds and responds to a linear 27-residue peptide natural ligand. The carboxyl-terminal region of this peptide assumes a helical conformation that occupies the peptide-binding cleft within the structurally complex disulphide-bonded amino-terminal domain of this receptor. The amino terminus of secretin is directed toward the core helical bundle domain of this receptor that seems to be structurally distinct from the analogous region of family A G protein-coupled receptors. This amino-terminal region of secretin is critical for its biological activity, to stimulate Gs coupling and the agonist-induced cAMP response. While the natural peptide ligand is known to span the two key receptor domains, with multiple residue-residue approximation constraints well established, the orientation of the receptor amino terminus relative to the receptor core helical bundle domain is still unclear. Fluorescence studies have established that the mid-region and carboxyl-terminal end of secretin are protected by the receptor peptide-binding cleft and the amino terminus of secretin is most exposed to the aqueous milieu as it is directed toward the receptor core, with the mid-region of the peptide becoming more exposed upon receptor activation. Like other family B peptide hormone receptors, the secretin receptor is constitutively present in a structurally specific homo-dimeric complex built around the lipid-exposed face of transmembrane segment four. This complex is important for facilitating G protein association and achieving the high affinity state of this receptor.
KW - RAMPs
KW - family B GPCR
KW - negative cooperativity
KW - photoaffinity labelling
KW - receptor dimerization
KW - secretin receptor
UR - http://www.scopus.com/inward/record.url?scp=84859724051&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859724051&partnerID=8YFLogxK
U2 - 10.1111/j.1476-5381.2011.01463.x
DO - 10.1111/j.1476-5381.2011.01463.x
M3 - Review article
C2 - 21542831
AN - SCOPUS:84859724051
SN - 0007-1188
VL - 166
SP - 18
EP - 26
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 1
ER -