Article

Spatial approximation between secretin residue five and the third extracellular loop of its receptor provides new insight into the molecular basis of natural agonist binding.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 13400 East Shea Blvd., Scottsdale, AZ 85259, USA.
Molecular pharmacology (Impact Factor: 4.53). 06/2008; 74(2):413-22. DOI: 10.1124/mol.108.047209
Source: PubMed

ABSTRACT The amino terminus of class II G protein-coupled receptors plays an important role in ligand binding and receptor activation. Understanding of the conformation of the amino-terminal domain of these receptors has been substantially advanced with the solution of nuclear magnetic resonance and crystal structures of this region of receptors for corticotrophin-releasing factor, pituitary adenylate cyclase-activating polypeptide, and gastric inhibitory polypeptide. However, the orientation of the amino terminus relative to the receptor core and how the receptor gets activated upon ligand binding remain unclear. In this work, we have used photoaffinity labeling to identify a critical spatial approximation between residue five of secretin and a residue within the proposed third extracellular loop of the secretin receptor. This was achieved by purification, deglycosylation, cyanogen bromide cleavage, and sequencing of labeled wild-type and mutant secretin receptors. This constraint has been used to refine our evolving molecular model of secretin docked at the intact receptor, which for the first time includes refined helical bundle and loop regions and reflects a peptide-binding groove within the receptor amino terminus that directs the amino terminus of the peptide toward the receptor body. This model is fully consistent with the endogenous agonist mechanism for class II G protein-coupled receptor activation, where ligand binding promotes the interaction of a portion of the receptor amino terminus with the receptor body to activate it.

0 Bookmarks
 · 
54 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The following research study is based on a micro-sociological approach to the phenomenon of immigration (Bös, 1998). It also focuses on the global view of international migration and emphasizes the fact that immigration can never be separated from emigration but they are two different processes of the same phenomenon. (Sayad, 2004). The primary purpose of the study is to explain inter-cultural coexistence not only from the perspective of immigrants but also from the viewpoint of the indigenous population of Fortezza, a small village in South Tirol, northern Italy. As the Latin preposition “inter” expresses, the study is trying to detect what is going on “between” the groups, where conflicting views exist despite the overlapping of the two worlds.
    Procedia - Social and Behavioral Sciences 01/2011; 15:1241-1247.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Class B guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) share heptahelical topology and signaling via coupling with heterotrimeric G proteins typical of the entire superfamily of GPCRs. However, they also exhibit substantial structural differences from the more extensively studied class A GPCRs. Even their helical bundle region, most conserved across the superfamily, is predicted to differ from that of class A GPCRs. Much is now known about the conserved structure of the amino-terminal domain of class B GPCRs, coming from isolated NMR and crystal structures, but the orientation of that domain relative to the helical bundle is unknown, and even less is understood about the conformations of the juxtamembranous amino-terminal tail or of the extracellular loops linking the transmembrane segments. We now review what is known about the structure and function of these regions of class B GPCRs. This comes from indirect analysis of structure-function relationships elucidated by mutagenesis and/or ligand modification and from the more direct analysis of spatial approximation coming from photoaffinity labeling and cysteine trapping studies. Also reviewed are the limited studies of structure of some of these regions. No dominant theme was recognized for the structures or functional roles of distinct regions of these juxtamembranous portions of the class B GPCRs. Therefore, it is likely that a variety of molecular strategies can be engaged for docking of agonist ligands and for initiation of conformational changes in these receptors that would be expected to converge to a common molecular mechanism for activation of intracellular signaling cascades.
    British Journal of Pharmacology 07/2013; · 5.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dimerization or oligomerization of G protein-coupled receptors (GPCRs) are known to modulate receptor functions in terms of ontogeny, ligand-oriented regulation, pharmacological diversity, signal transduction, and internalization. Class B GPCRs are receptors to a family of hormones including secretin, growth hormone-releasing hormone, vasoactive intestinal polypeptide and parathyroid hormone, among others. The functional implications of receptor dimerization have extensively been studied in class A GPCRs, while less is known regarding its function in class B GPCRs. This article reviews receptor oligomerization in terms of the early evidence and current understanding particularly of class B GPCRs.
    Frontiers in Endocrinology 01/2012; 3:175.