Trends in Biochemical Sciences
ReviewPassing the baton in class B GPCRs: peptide hormone activation via helix induction?
Section snippets
Class B GPCRs: a family of peptide hormone receptors
G-protein-coupled receptors (GPCRs) constitute a large family of transmembrane receptors that mediate transduction of an enormous variety of extracellular stimuli across cell membranes. Stimuli range from light, ions, nucleotides, organic volatiles, neurotransmitters and hormones through to peptides and proteins. Phylogenetically, GPCRs can be divided into at least five receptor classes (or families), of which class A represents the largest group (∼700 members, also termed the rhodopsin
The class B GPCR ligands: peptide hormones with α-helical propensities
The first X-ray crystal structure determination of glucagon in 1975 revealed a helical conformation for the hormone [26]. Later, NMR structural analyses, however, indicated that glucagon was disordered in solution [27]. This behaviour was also observed for PTH, which in solution exhibits limited secondary structure 28, 29 but is helical in protein crystals [30]. It is now established that most class B ligands, including GLP-1 and its lizard homologue exendin-4 31, 32, GIP [33], PACAP [21], CRF
The extracellular ligand-binding domains: one fold serves all?
Elucidation of the NMR structure of CRFR2β-ECD [61] revealed a core domain structure consisting of two central antiparallel β-sheets stabilized by three intramolecular disulphide bridges – a topology that resembles the short consensus repeat fold commonly found in proteins of the complement system [62]. With the structure determination of two further ECDs, PAC1Rs-ECD (using NMR) [21] and GIPR-ECD [22], the first crystal structure within this class, it became apparent that the ECD fold includes
Ligand binding by the ECDs: gripping the baton
Six of the recently solved class B ECD structures were elucidated in complex with a ligand: the solution structures of murine CRFR2β-ECD bound to the synthetic antagonist astressin [20]; PAC1Rs in complex with the antagonist PACAP6–38 [21]; the crystal structures of GIPR-ECD bound to its natural peptide hormone GIP1–42 [22]; GLP-1R-ECD in complex with the antagonist exendin-49–39 [23]; PTH1R-ECD bound to the truncated ligand PTH15–34 [24]; and two structures of CRFR1 in complex with the
Presenting the baton: evidence for α-helix formation during receptor binding
To recapitulate, the secretin family peptide hormones tend to be disordered in aqueous solution, but they are prone to adopt α-helical structures depending upon the ambient conditions or molecular environment. The ECD complex structures clearly show that this helical propensity of the isolated ligands translates into well-defined α-helical structures upon binding to the receptor ECD (Figure 2a). For most of the complexes, truncated peptides were used for structure determination (e.g. PTH15–34,
Passing the baton: a model for class B GPCR activation
In combination with the current data on class A GPCRs, the helix formation observed upon ECD binding enables the formulation of an attractive mechanical model for class B GPCR activation (Figure 5). We suggest that binding of a peptide hormone to its cognate ECD, driven largely by the burial of hydrophobic residues within the ligand-binding groove, would result in α-helix formation in the peptide. Indeed, it has recently been suggested that the presence of helix-capping residues in the
Going into the next lap: concluding remarks and future prospects
The recent flurry of class B ECD structures sheds light on their interactions with cognate ligands and provides first insights into the initial steps of class B GPCR activation. The common secretin family recognition fold acts as a capturing module for class B GPCR ligands, facilitating their simultaneous folding into an α-helix. This, in turn, suggests an activation mechanism in which the ECD presents a well-structured α-helical ligand to the receptor transmembrane helix domain, generating
Acknowledgements
Work in our laboratories is supported by the Landesexzellenzinitiative Sachsen-Anhalt ‘Strukturen und Mechanismen der biologischen Informationsverarbeitung’ (www.exzellenznetzwerk-biowissenschaften.uni-halle.de) as well as the DFG Sonderforschungsbereich 610 ‘Protein-Zustände mit zellbiologischer und medizinischer Relevanz’ (www.sfb610.de). The number of references cited in this article has been restricted according to TiBS policy; we apologize to those whose work has been left unacknowledged
References (80)
The biology of incretin hormones
Cell Metab.
(2006)Neuroprotection: a comparative view of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide
Peptides
(2007)- et al.
The CRF peptide family and their receptors: yet more partners discovered
Trends Pharmacol. Sci.
(2002) Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain
J. Biol. Chem.
(2008)Molecular recognition of corticotropin-releasing factor by its G-protein-coupled receptor CRFR1
J. Biol. Chem.
(2008)Conformation of glucagon in a lipid-water interphase by 1H nuclear magnetic resonance
J. Mol. Biol.
(1983)Solution structures of human parathyroid hormone fragments hPTH(1-34) and hPTH(1-39) and bovine parathyroid hormone fragment bPTH(1-37)
Biochem. Biophys. Res. Commun.
(2000)Crystal structure of human parathyroid hormone 1-34 at 0.9-A resolution
J. Biol. Chem.
(2000)NMR and alanine scan studies of glucose-dependent insulinotropic polypeptide in water
J. Biol. Chem.
(2006)Structural determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic α-helix
J. Biol. Chem.
(2006)
GIP(6-30amide) contains the high affinity binding region of GIP and is a potent inhibitor of GIP1-42 action in vitro
Regul. Pept.
Identification of a bioactive domain in the amino-terminus of glucose-dependent insulinotropic polypeptide (GIP)
Biochim. Biophys. Acta
Molecular properties of the PTH/PTHrP receptor
Trends Endocrinol. Metab.
The isolated N-terminal domain of the glucagon-like peptide-1 (GLP-1) receptor binds exendin peptides with much higher affinity than GLP-1
J. Biol. Chem.
A soluble form of the first extracellular domain of mouse type 2β corticotropin-releasing factor receptor reveals differential ligand specificity
J. Biol. Chem.
Mechanisms of peptide and nonpeptide ligand binding to Class B G-protein-coupled receptors
Drug Discov. Today
Full activation of chimeric receptors by hybrids between parathyroid hormone and calcitonin. Evidence for a common pattern of ligand-receptor interaction
J. Biol. Chem.
Critical contributions of amino-terminal extracellular domains in agonist binding and activation of secretin and vasoactive intestinal polypeptide receptors. Studies of chimeric receptors
J. Biol. Chem.
The isolated N-terminal extracellular domain of the glucagon-like peptide-1 (GLP)-1 receptor has intrinsic binding activity
FEBS Lett.
In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor
Biophys. Chem.
Three-dimensional structure of a complement control protein module in solution
J. Mol. Biol.
Distinct structural and functional roles of conserved residues in the first extracellular domain of receptors for corticotropin-releasing factor and related G-protein-coupled receptors
J. Biol. Chem.
Search for α-helical propensity in the receptor-bound conformation of glucagon-like peptide-1
Bioorg. Med. Chem.
Class-B GPCR activation: is ligand helix-capping the key?
Trends Biochem. Sci.
The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure
J. Mol. Biol.
Spatial approximation between the amino terminus of a peptide agonist and the top of the sixth transmembrane segment of the secretin receptor
J. Biol. Chem.
Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus
J. Biol. Chem.
Parathyroid hormone and parathyroid hormone-related peptide, and their receptors
Biochem. Biophys. Res. Commun.
Dimerization in the absence of higher-order oligomerization of the G protein-coupled secretin receptor
Biochim. Biophys. Acta
The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints
Mol. Pharmacol.
Structural diversity of G protein-coupled receptors and significance for drug discovery
Nat. Rev. Drug Discov.
New drugs for the treatment of diabetes: part II: incretin-based therapy and beyond
Circulation
Drug insight: existing and emerging therapies for osteoporosis
Nat. Clin. Pract. Endocrinol. Metab.
The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily
Endocr. Rev.
Rational design, synthesis, and biological evaluation of novel growth hormone releasing factor analogues
Biopolymers
Corticotropin-releasing factor antagonists: recent advances and exciting prospects for the treatment of human diseases
Curr. Opin. Drug Discov. Devel.
Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity
Diabetologia
Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV
Endocrinology
Crystal structure of rhodopsin: a G protein-coupled receptor
Science
GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function
Science
Cited by (169)
Conjugation with glucagon like peptide-1 enables targeted protein degradation
2023, Bioorganic ChemistrySingle-molecule analysis reveals that a glucagon-bound extracellular domain of the glucagon receptor is dynamic
2023, Journal of Biological ChemistryNaturally occurring mutations in G protein-coupled receptors associated with obesity and type 2 diabetes mellitus
2022, Pharmacology and TherapeuticsExpression, purification and molecular dynamics simulation of extracellular domain of glucagon-like peptide-2 receptor linked to teduglutide
2021, International Journal of Biological Macromolecules