Modeling Secretin Class B Family GPCRs

The secretin (Class B) family comprises at least 15 GPCRs that share significant sequence similarity and an extracellular hormone-binding amino-terminal domain. Structures of isolated amino-termini for corticotropin-releasing factor (CRF), pituitary adenylate cyclase-activating polypeptide (hPAC1), gastric inhibitory polypeptide (GIP), and parathyroid hormone (PTH1) receptors have been recently solved by NMR and crystallography -127-129] . Though highly divergent in amino acid sequence, the Class B extracellular domains share a similar protein fold of about ~90 amino acids, stabilized by three con served disulfide bonds, allowing each to interact with their respective hormone peptides in a relatively shallow binding groove. The latter three structures were characterized in complex with peptide hormones and may serve as structural templates for the rational design of orthosteric agonists and antagonists.

Computational modeling of the full-length secretin receptor was recently performed to investigate interactions among the receptor 7TM core, receptor N-terminus, and peptide ligand [130-132]. The complete model was constructed using the crystallographic N-terminal domain structures of CRF and GIP receptors [127, 128], homology models of the TM helical bundle, and distance constraints derived from photoaffinity labeling and FRET experiments [131-133]. The modeling indicates that the extracellular domain of the secretin receptor directs the peptide N-terminus toward the opening in the TM7 helical bundle. The refined model also suggests details of the receptor 7TM core interaction with a Trp-Asp-Asn epitope (W48D49N50) in the receptor N-terminal domain, known to be involved in activation of several Class B GPCRs (Fig. 15.7).

Figure 15.7 A secretin receptor model, generated by energy-based peptide docking. The model accommodates 10 photoaffinity labeling constraints and the three disulfide bonds demonstrated to exist in the secretin receptor. The full receptor is represented in orange ribbon, the secretin peptide is colored blue-red from the amino-terminus to the carboxyl terminus, and the 10 photoaffinity labeling constraints are represented as green dotted lines. The cross-linked residues on the secretin peptide are displayed in thin sticks. Residues of the secretin peptide are labeled in black. The proposed Nilerminal domain epitope, implicated in secretin receptor activation (amino acids

Figure 15.7 A secretin receptor model, generated by energy-based peptide docking. The model accommodates 10 photoaffinity labeling constraints and the three disulfide bonds demonstrated to exist in the secretin receptor. The full receptor is represented in orange ribbon, the secretin peptide is colored blue-red from the amino-terminus to the carboxyl terminus, and the 10 photoaffinity labeling constraints are represented as green dotted lines. The cross-linked residues on the secretin peptide are displayed in thin sticks. Residues of the secretin peptide are labeled in black. The proposed Nilerminal domain epitope, implicated in secretin receptor activation (amino acids

Isoproterenol

Isoproterenol

W48D49N50), is shown in CPK.

Though the open shape and flexibility of the orthosteric pocket favor design of peptide-like ligands, small molecule modulators are sought that target allosteric sites in either the TM helical bundle or the interface between the extracellular and TM domains. In the past decade, a number of small molecule allosteric modulators of Class B GPCRs have been reported, most of them antagonists of the CRF (CRF1) [134-138] . Some of these orally available compounds have shown promising results in preclinical models of anxiety and depression [139], and initial clinical studies [140], suggesting the general utility of targeting allosteric sites in Class B GPCR modulation.

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