scholarly journals Transmembrane Segment IV Contributes a Functionally Important Interface for Oligomerization of the Class II G Protein-coupled Secretin Receptor

2007 ◽  
Vol 282 (42) ◽  
pp. 30363-30372 ◽  
Author(s):  
Kaleeckal G. Harikumar ◽  
Delia I. Pinon ◽  
Laurence J. Miller
Keyword(s):  
G Protein ◽  
Class Ii ◽  
Transmembrane Segment ◽  
Secretin Receptor ◽  
G Protein Coupled

Structural basis of natural ligand binding and activation of the Class II G-protein-coupled secretin receptor

2007 ◽  
Vol 35 (4) ◽  
pp. 709-712 ◽  
Author(s):  
L.J. Miller ◽  
M. Dong ◽  
K.G. Harikumar ◽  
F. Gao
Keyword(s):  
G Protein ◽  
Disulfide Bonds ◽  
Class Ii ◽  
Structural Basis ◽  
Photoaffinity Labelling ◽  
The Core ◽  
Natural Ligand ◽  
Secretin Receptor ◽  
N Terminus ◽  
G Protein Coupled

The secretin receptor is prototypic of Class II GPCRs (G-protein-coupled receptors), based on its structural and functional characteristics and those of its natural agonist ligand. Secretin represents a linear 27-residue peptide with diffuse pharmacophoric domain. The secretin receptor includes the typical signature sequences for this receptor family within its predicted transmembrane segments and the highly conserved six cysteine residues contributing to three intradomain disulfide bonds within its long N-terminus. This domain is critical for secretin binding based on receptor mutagenesis and photoaffinity labelling studies. Full agonist analogues of secretin incorporating a photolabile moiety at various positions throughout the pharmacophore covalently label residues within this region, while only N-terminal probes have labelled the core helical bundle domain. Combining insights coming from receptor structural studies, peptide structure–activity relationship considerations, photoaffinity labelling, and application of fluorescence techniques has resulted in the development of a working model of the secretin–receptor complex. This supports the initial docking of the peptide agonist within a cleft in the receptor N-terminus, providing the opportunity for an endogenous sequence within that domain to interact with the core of the receptor. This interaction is believed to be key in the molecular basis of conformational change associated with activation of this receptor. The site of action of this endogenous agonist could also provide a possible target for small molecule agonists to act.

scholarly journals A Role for Receptor Kinases in the Regulation of Class II G Protein-coupled Receptors

1998 ◽  
Vol 273 (12) ◽  
pp. 6756-6762 ◽  
Author(s):  
Michael A. Shetzline ◽  
Richard T. Premont ◽  
Julia K. L. Walker ◽  
Steven R. Vigna ◽  
Marc G. Caron
Keyword(s):  
G Protein ◽  
Class Ii ◽  
G Protein Coupled Receptors ◽  
Receptor Kinases ◽  
G Protein Coupled

Constitutive activation of the human VIP1/PACAP receptor, a member of the new class II family of G protein-coupled receptors

1998 ◽  
Vol 114 ◽  
pp. A1144
Author(s):  
P. Gaudin ◽  
J.J. Maoret ◽  
A. Couvineau ◽  
C. Rouyer-Fessard ◽  
M. Laburthe
Keyword(s):  
G Protein ◽  
Class Ii ◽  
G Protein Coupled Receptors ◽  
Constitutive Activation ◽  
New Class ◽  
G Protein Coupled

The orthosteric agonist-binding pocket in the prototypic class B G-protein-coupled secretin receptor

2013 ◽  
Vol 41 (1) ◽  
pp. 154-158 ◽  
Author(s):  
Laurence J. Miller ◽  
Maoqing Dong
Keyword(s):  
G Protein ◽  
Fluorescence Analysis ◽  
Binding Pocket ◽  
Rational Development ◽  
Secretin Receptor ◽  
Natural Ligands ◽  
Class B ◽  
G Protein Coupled ◽  
Moderate Length ◽  
Activity Series

Class B GPCRs (G-protein-coupled receptors) share heptahelical topology and G-protein binding with other superfamily members, yet have unique structures and modes of activation. Natural ligands for these receptors are moderate-length peptides with C-terminal α-helices. NMR and crystal structures of the peptide-bound disulfide-bonded receptor N-terminal domains demonstrate that these helices occupy a conserved groove; however, the details of this interaction vary from one receptor to another. In this review, we focus on the prototypic secretin receptor and use extensive intrinsic photoaffinity labelling, structure–activity series, alanine-replacement mutagenesis and fluorescence analysis to define the molecular basis for this interaction. Additionally, experimental validation of predictions coming from in silico molecular modelling has provided a basis for enhancement of binding affinity. Such insights will be useful in the rational development of drugs acting at this important group of targets.

scholarly journals Molecular Basis of Association of Receptor Activity-Modifying Protein 3 with the Family B G Protein-Coupled Secretin Receptor

Biochemistry ◽  
2009 ◽  
Vol 48 (49) ◽  
pp. 11773-11785 ◽  
Author(s):  
Kaleeckal G. Harikumar ◽  
John Simms ◽  
George Christopoulos ◽  
Patrick M. Sexton ◽  
Laurence J. Miller
Keyword(s):  
G Protein ◽  
Molecular Basis ◽  
Receptor Activity ◽  
Secretin Receptor ◽  
The Family ◽  
G Protein Coupled
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