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G-protein-coupled receptors (GPCR) are a family of membrane receptors that play important roles in the regulation of various physiological phenomena. LPA receptors (LPA1-6) are members of the class A GPCRs, which transduce a lysophosphatidic acid (LPA) signal across the cell membrane and evoke various responses, including cellular survival, proliferation, differentiation, and migration. The crystal structure of LPA6 revealed a gap between its transmembrane helices (TMs), which is opened toward the membrane side. This led to the proposal of the "lateral access model," in which its lipophilic ligand directly enters the binding pocket through the gap structure at the membrane. In this study, we performed molecular dynamics (MD) simulations and Markov state model (MSM) analyses of LPA6 and LPA, to elucidate the long timescale dynamics of the ligand binding process. The results from the 71.4-μs MD simulation suggested that the flexibility of the TMs constituting the gap structure enables the lateral entrance of the ligand, and the key interactions between the receptor and ligand facilitate the transition state of the ligand binding process. [ABSTRACT FROM AUTHOR]

Newly synthesized membrane proteins must be accurately inserted into the membrane, folded and assembled for proper functioning. The protein YidC inserts its substrates into the membrane, thereby facilitating membrane protein assembly in bacteria; the homologous proteins Oxa1 and Alb3 have the same function in mitochondria and chloroplasts, respectively. In the bacterial cytoplasmic membrane, YidC functions as an independent insertase and a membrane chaperone in cooperation with the translocon SecYEG. Here we present the crystal structure of YidC from Bacillus halodurans, at 2.4 Å resolution. The structure reveals a novel fold, in which five conserved transmembrane helices form a positively charged hydrophilic groove that is open towards both the lipid bilayer and the cytoplasm but closed on the extracellular side. Structure-based in vivo analyses reveal that a conserved arginine residue in the groove is important for the insertion of membrane proteins by YidC. We propose an insertion mechanism for single-spanning membrane proteins, in which the hydrophilic environment generated by the groove recruits the extracellular regions of substrates into the low-dielectric environment of the membrane. [ABSTRACT FROM AUTHOR]