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Int. J. Mol. Sci. 2013, 14(2), 2788-2807; doi:10.3390/ijms14022788

Structural Characterization of an LPA1 Second Extracellular Loop Mimetic with a Self-Assembling Coiled-Coil Folding Constraint

1
Department of Chemistry and Computational Research on Materials Institute, The University of Memphis, Memphis, TN 38152-3550, USA
2
Department of Chemistry, Christian Brothers University, Memphis, TN 38104, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 11 October 2012 / Revised: 16 November 2012 / Accepted: 24 January 2013 / Published: 29 January 2013
(This article belongs to the Special Issue Phospholipids: Molecular Sciences 2012)
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Abstract

G protein-coupled receptor (GPCR) structures are of interest as a means to understand biological signal transduction and as tools for therapeutic discovery. The growing number of GPCR crystal structures demonstrates that the extracellular loops (EL) connecting the membrane-spanning helices show tremendous structural variability relative to the more structurally-conserved seven transmembrane α-helical domains. The EL of the LPA1 receptor have not yet been conclusively resolved, and bear limited sequence identity to known structures. This study involved development of a peptide to characterize the intrinsic structure of the LPA1 GPCR second EL. The loop was embedded between two helices that assemble into a coiled-coil, which served as a receptor-mimetic folding constraint (LPA1-CC-EL2 peptide). The ensemble of structures from multi-dimensional NMR experiments demonstrated that a robust coiled-coil formed without noticeable deformation due to the EL2 sequence. In contrast, the EL2 sequence showed well-defined structure only near its C-terminal residues. The NMR ensemble was combined with a computational model of the LPA1 receptor that had previously been validated. The resulting hybrid models were evaluated using docking. Nine different hybrid models interacted with LPA 18:1 as expected, based on prior mutagenesis studies, and one was additionally consistent with antagonist affinity trends. View Full-Text
Keywords: G protein-coupled receptor; GPCR; lysophosphatidic acid; LPA; NMR; GPCR segment model G protein-coupled receptor; GPCR; lysophosphatidic acid; LPA; NMR; GPCR segment model
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Young, J.K.; Clayton, B.T.; Kikonyogo, A.; Pham, T.-C.T.; Parrill, A.L. Structural Characterization of an LPA1 Second Extracellular Loop Mimetic with a Self-Assembling Coiled-Coil Folding Constraint. Int. J. Mol. Sci. 2013, 14, 2788-2807.

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