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

Laurence J Miller, Maoqing Dong

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 peptidebound 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.

Original languageEnglish (US)
Pages (from-to)154-158
Number of pages5
JournalBiochemical Society Transactions
Volume41
Issue number1
DOIs
StatePublished - Feb 2013

Fingerprint

Mutagenesis
Molecular modeling
G-Protein-Coupled Receptors
GTP-Binding Proteins
Protein Binding
Disulfides
Alanine
Computer Simulation
Labeling
Crystal structure
Fluorescence
Chemical activation
Nuclear magnetic resonance
Topology
Ligands
Peptides
Pharmaceutical Preparations
secretin receptor
polypeptide C

Keywords

  • GPCR (G-protein-coupled receptor)
  • Ligand binding
  • Receptor conformation

ASJC Scopus subject areas

  • Biochemistry

Cite this

The orthosteric agonist-binding pocket in the prototypic class B G-protein-coupled secretin receptor. / Miller, Laurence J; Dong, Maoqing.

In: Biochemical Society Transactions, Vol. 41, No. 1, 02.2013, p. 154-158.

Research output: Contribution to journalArticle

@article{7d5781f61d254cc889a64188cfe39913,
title = "The orthosteric agonist-binding pocket in the prototypic class B G-protein-coupled secretin receptor",
abstract = "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 peptidebound 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.",
keywords = "GPCR (G-protein-coupled receptor), Ligand binding, Receptor conformation",
author = "Miller, {Laurence J} and Maoqing Dong",
year = "2013",
month = "2",
doi = "10.1042/BST20120204",
language = "English (US)",
volume = "41",
pages = "154--158",
journal = "Biochemical Society Transactions",
issn = "0300-5127",
publisher = "Portland Press Ltd.",
number = "1",

}

TY - JOUR

T1 - The orthosteric agonist-binding pocket in the prototypic class B G-protein-coupled secretin receptor

AU - Miller, Laurence J

AU - Dong, Maoqing

PY - 2013/2

Y1 - 2013/2

N2 - 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 peptidebound 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.

AB - 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 peptidebound 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.

KW - GPCR (G-protein-coupled receptor)

KW - Ligand binding

KW - Receptor conformation

UR - http://www.scopus.com/inward/record.url?scp=84873102925&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873102925&partnerID=8YFLogxK

U2 - 10.1042/BST20120204

DO - 10.1042/BST20120204

M3 - Article

VL - 41

SP - 154

EP - 158

JO - Biochemical Society Transactions

JF - Biochemical Society Transactions

SN - 0300-5127

IS - 1

ER -