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

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; in revised form: 16 November 2012 / Accepted: 24 January 2013 / Published: 29 January 2013
(This article belongs to the Special Issue Phospholipids: Molecular Sciences 2012)
PDF Full-text Download PDF Full-Text [4068 KB, uploaded 29 January 2013 09:35 CET]
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.
Keywords: G protein-coupled receptor; GPCR; lysophosphatidic acid; LPA; NMR; GPCR segment model

Article Statistics

Load and display the download statistics.

Citations to this Article

Cite This Article

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.

AMA Style

Young JK, Clayton BT, Kikonyogo A, Pham T-CT, Parrill AL. Structural Characterization of an LPA1 Second Extracellular Loop Mimetic with a Self-Assembling Coiled-Coil Folding Constraint. International Journal of Molecular Sciences. 2013; 14(2):2788-2807.

Chicago/Turabian Style

Young, John K.; Clayton, Benjamin T.; Kikonyogo, Alexandra; Pham, Truc-Chi T.; Parrill, Abby L. 2013. "Structural Characterization of an LPA1 Second Extracellular Loop Mimetic with a Self-Assembling Coiled-Coil Folding Constraint." Int. J. Mol. Sci. 14, no. 2: 2788-2807.

Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert