Trends in Pharmacological Sciences
ReviewInsights into the structure of class B GPCRs
Section snippets
Understanding the function of class B GPCRs from their structure
Class B G protein-coupled receptors (GPCRs), also referred to as the secretin family of GPCRs, include receptors for 15 peptide hormones, which can be grouped into five subfamilies based on their physiological role (see Table 1 for an overview) [1]. These receptors are important drug targets in many human diseases, including diabetes, osteoporosis, obesity, cancer, neurodegeneration, cardiovascular disease, headache, and psychiatric disorders. However, the identification of small-molecule oral
Comparison of the CRF1 and GCGR structures
Using a mutagenesis approached called ‘conformational thermostabilization’ described earlier [12], a crystallizable version of the TMD of the human CRF1 receptor (also known as CRHR1) with increased thermostability and bias towards the inactive conformation was generated, and its structure has recently been determined by X-ray crystallography in complex with the 2-aryloxy-4-alkylaminopyridine CP-376395 [13], a small-molecule antagonist [10] (Figures 1A). Simultaneously, the structure of the TMD
Extracellular domain structures
The crystal structures and NMR structures of the ECDs of different class B GPCRs (Figure 2A) show that this domain has a conserved fold that includes two central antiparallel β-sheets and an N-terminal α-helix interconnected by several loops and stabilized by three conserved disulfide bonds. Ten of the eleven ECD–peptide ligand complexes show a similar binding mode in which the C terminus of the peptide ligand adopts an α-helical conformation that binds between the two β-sheets of the ECD (
Peptide ligand recognition by the TMD of class B GPCRs
There has been no clear consensus on the binding site location of peptide ligands in the TMDs of class B GPCRs; its location has been associated either with the extracellular loop regions 2, 6 or with a pocket in the TMD 25, 26. Combination of previous structural information on ECD–ligand complexes (Table 1, Figure 2) with the recent GCGR and CRF1 TMD crystal structures allowed the construction of a full receptor–ligand model [11] (Figure 4A). This model can account for the extensive
Druggability of the orthosteric and small-molecule binding sites
Despite the lack of sequence conservation, comparison of the CRF1 and GCGR structures with those of class A GPCR shows that the orientations and positions of TM helices are conserved between the two classes 10, 11 (Figure 3B). This common GPCR fold is stabilized by similar regions of contacts between TM helices in both classes, but involves distinct patterns of conserved residues in class A [8] and class B [11] GPCRs (Figures 3A and 4B). The distances between the extracellular ends of TM2 and
Concluding remarks
The GCGR and CRF1 crystal structures show distinct structural features and different binding pockets compared to class A GPCRs, and give new insights into the molecular details of peptide and small-molecule binding to class B GPCRs. The first two crystal structures of the TM domains of class B GPCRs provide a structural framework that will enable the design of biochemical and biophysical experiments detailing the complex structure of this class of receptors, and facilitate the design of
Acknowledgements
This work was supported by PSI:Biology (grant U54 GM094618 to R.C.S.), the Chinese Ministry of Health (grants 2012ZX09304-011 and 2013ZX09507002 to M.-W.W.), the Shanghai Science and Technology Development Fund (grant 11DZ2292200 to M.-W.W.), the Novo Nordisk-Chinese Academy of Sciences Research Fund (grant NNCAS-2011-7 to M.-W.W.), the Thousand Talents Program in China (to M.-W.W.), and European Cooperation in Science and Technology (COST) Action CM1207, GPCR-Ligand Interactions, Structures,
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These authors contributed equally.