2dco
From Proteopedia
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S1P4 First Extracellular Loop Peptidomimetic
Overview
G protein-coupled receptors (GPCRs) control fundamental aspects of human, physiology and behaviors. Knowledge of their structures, especially for, the loop regions, is limited and has principally been obtained from, homology models, mutagenesis data, low resolution structural studies, and, high resolution studies of peptide models of receptor segments. We, developed an alternate methodology for structurally characterizing GPCR, loops, using the human S1P(4) first extracellular loop (E1) as a model, system. This methodology uses computational peptide designs based on, transmembrane domain (TM) model structures in combination with CD and NMR, spectroscopy. The characterized peptides contain segments that mimic the, self-assembling extracellular ends of TM 2 and TM 3 separated by E1, including residues R3.28(121) and E3.29(122) that are required for, sphingosine 1-phosphate (S1P) binding and receptor activation in the, S1P(4) receptor. The S1P(4) loop mimetic peptide interacted specifically, with an S1P headgroup analog, O-phosphoethanolamine (PEA), as evidenced by, PEA-induced perturbation of disulfide cross-linked coiled-coil first, extracellular loop mimetic (CCE1a) (1)H and (15)N backbone amide chemical, shifts. CCE1a was capable of weakly binding PEA near biologically relevant, residues R29 and E30, which correspond to R3.28 and E3.29 in the, full-length S1P(4) receptor, confirming that it has adopted a biologically, relevant conformation. We propose that the combination of coiled-coil TM, replacement and conformational stabilization with an interhelical, disulfide bond is a general design strategy that promotes native-like, structure for loops derived from GPCRs. (c) 2007 Wiley Periodicals, Inc., Biopolymers 86: 298-310, 2007.This article was originally published online, as an accepted preprint. The "Published Online" date corresponds to the, preprint version. You can request a copy of the preprint by emailing the, Biopolymers editorial office at biopolymers@wiley.com.
About this Structure
2DCO is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Peptide design and structural characterization of a GPCR loop mimetic., Pham TC, Kriwacki RW, Parrill AL, Biopolymers. 2007 Jul;86(4):298-310. PMID:17443712
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