Toward the three-dimensional structure and lysophosphatidic acid binding characteristics of the LPA(4)/p2y(9)/GPR23 receptor: a homology modeling study.

Lysophosphatidic acid (LPA) is a naturally occurring phospholipid that initiates a broad array of biological processes, including those involved in cell proliferation, survival and migration via activation of specific G protein-coupled receptors located on the cell surface. To date, at least five receptor subtypes (LPA(1-5)) have been identified. The LPA(1-3) receptors are members of the endothelial cell differentiation gene (Edg) family. LPA(4), a member of the purinergic receptor family, and the recently identified LPA(5) are structurally distant from the canonical Edg LPA(1-3) receptors. LPA(4) and LPA(5) are linked to G(q), G(12/13) and G(s) but not G(i), while LPA(1-3) all couple to G(i) in addition to G(q) and G(12/13). There is also evidence that LPA(4) and LPA(5) are functionally different from the Edg LPA receptors. Computational modeling has provided useful information on the structure-activity relationship (SAR) of the Edg LPA receptors. In this work, we focus on the initial analysis of the structural and ligand-binding properties of LPA(4), a prototype non-Edg LPA receptor. Three homology models of the LPA(4) receptor were developed based on the X-ray crystal structures of the ground state and photoactivated bovine rhodopsin and the recently determined human beta(2)-adrenergic receptor. Docking studies of LPA in the homology models were then conducted, and plausible LPA binding loci were explored. Based on these analyses, LPA is predicted to bind to LPA(4) in an orientation similar to that reported for LPA(1-3), but through a different network of hydrogen bonds. In LPA(1-3), the ligand polar head group is reported to interact with residues at positions 3.28, 3.29 and 7.36, whereas three non-conserved amino acid residues, S114(3.28), T187(EL2) and Y265(6.51), are predicted to interact with the polar head group in the LPA(4) receptor models.