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Passing the baton in class B GPCRs: peptide hormone activation via helix induction?

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G-protein-coupled receptors (GPCRs) represent the largest constellation of validated drug targets. Crystal structures of class A GPCRs have facilitated major advances in understanding the principles underlying GPCR activation. By contrast, relatively little is known about class B GPCRs, a family of receptors for a variety of therapeutically relevant peptide hormones. Encouraging progress has recently been made through the structural elucidation of several extracellular hormone-binding domains of class B GPCRs in complex with their natural ligands or synthetic analogues. The structures reveal similar modes of ligand binding, with concomitant α-helical structuring of the ligand. The latter suggests an attractive mechanical model for class B GPCR activation.

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

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