Structural basis of natural ligand binding and activation of the Class II G-protein-coupled secretin receptor.

Abstract:

:The secretin receptor is prototypic of Class II GPCRs (G-protein-coupled receptors), based on its structural and functional characteristics and those of its natural agonist ligand. Secretin represents a linear 27-residue peptide with diffuse pharmacophoric domain. The secretin receptor includes the typical signature sequences for this receptor family within its predicted transmembrane segments and the highly conserved six cysteine residues contributing to three intradomain disulfide bonds within its long N-terminus. This domain is critical for secretin binding based on receptor mutagenesis and photoaffinity labelling studies. Full agonist analogues of secretin incorporating a photolabile moiety at various positions throughout the pharmacophore covalently label residues within this region, while only N-terminal probes have labelled the core helical bundle domain. Combining insights coming from receptor structural studies, peptide structure-activity relationship considerations, photoaffinity labelling, and application of fluorescence techniques has resulted in the development of a working model of the secretin-receptor complex. This supports the initial docking of the peptide agonist within a cleft in the receptor N-terminus, providing the opportunity for an endogenous sequence within that domain to interact with the core of the receptor. This interaction is believed to be key in the molecular basis of conformational change associated with activation of this receptor. The site of action of this endogenous agonist could also provide a possible target for small molecule agonists to act.

journal_name

Biochem Soc Trans

authors

Miller LJ,Dong M,Harikumar KG,Gao F

doi

10.1042/BST0350709

subject

Has Abstract

pub_date

2007-08-01 00:00:00

pages

709-12

issue

Pt 4

eissn

0300-5127

issn

1470-8752

pii

BST0350709

journal_volume

35

pub_type

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