2LQ4

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

Summary for 2LQ4

• Entry DOI: 10.2210/pdb2lq4/pdb
• NMR Information: BMRB: 17993
• Descriptor: Lysophosphatidic acid receptor 1 (1 entity in total)
• Functional Keywords: gpcr, g protein-coupled receptor, de novo protein
• Biological source: artificial gene
• Total number of polymer chains: 1
• Total formula weight: 9340.96

Authors

Young, J.K. (deposition date: 2012-02-23, release date: 2013-01-09, Last modification date: 2024-05-15)

Primary citation

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

PubMed 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 LPA(1) 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 LPA(1) GPCR second EL. The loop was embedded between two helices that assemble into a coiled-coil, which served as a receptor-mimetic folding constraint (LPA(1)-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 LPA(1) 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.

PubMed: 23434648
DOI: 10.3390/ijms14022788

Experimental method

SOLUTION NMR