Molecular Mechanism of Ligand Recognition and Activation of Lysophosphatidic Acid Receptor LPAR6

The study presents the cryoelectron microscopy structure of LPA-bound human LPAR6, revealing a unique ligand binding and recognition mode distinct from LPAR1. LPA forms an extensive polar interaction network with key polar residues on the extracellular side of transmembrane helix 5-6 and the extracellular loop 2. The findings suggest that EDG and non-EDG families use different modes for LPA binding. Functional mutagenesis studies validate these structural observations. The research uncovers mechanisms of LPAR6 activation and G-protein coupling, providing a foundation for understanding LPAR6 signaling and aiding in the design of compounds targeting LPAR6, which is significant for hair loss and cancer progression.