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• W2896089314 abstract "As major regulators of mammalian physiology, G protein-coupled receptors (GPCRs) for the structurally related lysophospholipids (LPLs) sphingosine 1-phosphate (S1P), lysophosphatidic acid (LPA), as well as other LPLs, are providing new insights into fundamental biology and genuine therapeutics. Despite their structural similarities, GPCRs for S1P and LPA do not show physiological promiscuity, indicating molecular selectivity. In an effort to clarify structural mechanisms underlying ligand recognition and discrimination, the LPL receptors S1P1, LPA1, and most recently, LPA6, have been crystallized, generating hypotheses regarding differential ligand delivery and accommodation. Novel secondary and tertiary structures revealed by the three crystal structures support emerging evidence suggesting that S1P, and possibly LPA, can act as biased agonists when bound to specific protein chaperones. Lysophospholipids (LPLs), particularly sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA), are bioactive lipid modulators of cellular homeostasis and pathology. The discovery and characterization of five S1P- and six LPA-specific G protein-coupled receptors (GPCRs), S1P1–5 and LPA1–6, have expanded their known involvement in all mammalian physiological systems. Resolution of the S1P1, LPA1, and LPA6 crystal structures has fueled the growing interest in these receptors and their ligands as targets for pharmacological manipulation. In this review, we have attempted to provide an integrated overview of the three crystallized LPL GPCRs with biochemical and physiological structure–function data. Finally, we provide a novel discussion of how chaperones for LPLs may be considered when extrapolating crystallographic and computational data toward understanding actual biological interactions and phenotypes. Lysophospholipids (LPLs), particularly sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA), are bioactive lipid modulators of cellular homeostasis and pathology. The discovery and characterization of five S1P- and six LPA-specific G protein-coupled receptors (GPCRs), S1P1–5 and LPA1–6, have expanded their known involvement in all mammalian physiological systems. Resolution of the S1P1, LPA1, and LPA6 crystal structures has fueled the growing interest in these receptors and their ligands as targets for pharmacological manipulation. In this review, we have attempted to provide an integrated overview of the three crystallized LPL GPCRs with biochemical and physiological structure–function data. Finally, we provide a novel discussion of how chaperones for LPLs may be considered when extrapolating crystallographic and computational data toward understanding actual biological interactions and phenotypes. a molecule that binds the orthosteric binding site and activates a GPCR by stabilizing it in an active conformation. Full agonists induce maximal activation of the receptor. LPL receptors differ in their ability to be fully activated by LPL (their agonists) with varying hydroxyl carbon chain length and head groups. a site distinct from the orthosteric binding pocket, at which binding of a molecule alters receptor conformation, modulating its activity. a molecule that binds the orthosteric (competitive) or allosteric (noncompetitive) site, blocking activation of the GPCR by stabilizing the inactive conformation, preventing coupling with and activation of G proteins or β arrestins and their respective downstream signaling pathways. a group of four proteins (two visual arrestins, β-arrestin 1, and β-arrestin 2) that are recruited to phosphorylated GPCR C-terminal tails. Arrestins can negatively regulate G protein signaling or initiate their own unique signaling cascades. also referred to as the temperature factor, B-factor refers to the uncertainty of an atom’s position in a crystal structure and is a measure of thermal motion. A region of the protein that can adopt multiple conformations in space will have a higher B-factor than regions with less flexibility and motion. Because it is a measure of uncertainty, structures of lower resolution will tend to have higher B-factors. in a GPCR, a specific sequence of phosphorylated residues recognized by arrestin proteins to initiate biased agonist signaling. P represents a phospho-serine or phospho-threonine and x can be any amino acid except proline in the second xx instance of either the PxPxxP/E/D (short bar code) or PxxPxxP/E/D (long bar code). The final residue can also be either aspartate or glutamate. Ballesteros–Weinstein generic numbering scheme for GPCR residues. The format of BW, ‘TM helix.XX’, gives the TM helix number followed by ‘XX’ as the residue number according to its distance from the most conserved residue of each TM helix, which is designated as ‘50’. For example, the BW number 7.50 indicates a residue on TM7 and is the most conserved residue at position 50, whereas residues 7.49 and 7.51 are the residues on either side of the conserved residue. The GPCRdb (http://www.gpcrdb.org/) has recently updated the numbering scheme based on structural alignments, designating residues that create a bulge in the structure with the same number as the preceding residue, appending a ‘1’ to the residue number (e.g., both human and zebrafish LPA6 have G5.461). BW labels in this review are based on updated BW nomenclature derived from PDB alignments on GPCRdb. Thus, some of the residue labels differ from those given in original reports. saturated hydrocarbon carbon chains have no double bonds, whereas the presence of at least one double bond makes a carbon chain unsaturated. Saturation or unsaturation of the carbon chain is indicated by the C:D notation, where the number in the C position is the number of carbon atoms in the chain and D is the number of double bonds, or unsaturations. Thus, 18:1 S1P or LPA have an 18-carbon chain backbone with a single double bond. A detailed explanation of IUPAC-IUB hydrocarbon chain and lipid nomenclature can be found here: http://www.sbcs.qmul.ac.uk/iupac/lipid/. an amino acid motif of cysteine (C), tryptophan (W), any single amino acid (x), and proline (P). a process whereby a GPCR with unknown ligand specificity – an ‘orphan’ – is matched to a natural, physiological ligand to establish functional identity. the most conserved form of this amino acid motif is DRY [aspartate (D), arginine (R), tyrosine (Y)]. Other forms are not as common but not rare, including ERY [glutamate (E) substituted for D], seen in S1P1, or DRF [phenylalanine (F) substituted for Y], seen in LPA6. The ERH [E substituted for D and histamine (H) substituted for Y] seen in LPA1 is far less common. a superfamily of heptahelical TM receptors sharing a common structure and conserved activation motifs. GPCRs transduce extracellular cues to intracellular signals by changing their conformation to recruit heterotrimeric G proteins, GPCR kinases (GRKs), or arrestins (e.g., visual or β arrestins). subgroup of lipids that includes S1P and LPA. The characterization as lysolipids stems from the loss of acyl chains from their parent compounds, but can also refer to early observations that some variants caused cell lysis. Both S1P and LPA have simple sphingoid or glycerol backbones, respectively, connecting phosphate head groups and saturated or unsaturated carbon chains, usually from C14 to C22, although shorter or longer chains can be found in some tissues. a site on the exterior (lipid-facing) portion of the GPCR to which ligands can bind before conformational changes allow ligands to move into the orthosteric binding pocket. an in silico method for integrating known structural and physical data and applying energetic restrictions to generate an atomistic model of the interactions between receptors and other molecules, such as ligands, the lipid membrane, signaling molecules, or other receptors. a chronic disease of the central nervous system (CNS), the causes of which are unknown, but likely involve a combination of factors involving the immune, nervous, and vascular systems. The development and progression of MS require activation of the immune system to attack cells and components of the CNS, which requires inflammatory activation of the vascular system. an amino acid motif of asparagine (N), proline (P), any two amino acids (xx), and tyrosine (Y). a 3D structure of TM helices, EC loops, and N-terminal residues where endogenous ligand(s) bind to propagate interactions by conserved motifs and other subtle, ligand- and receptor-specific events (e.g., H2O ions or lipid interactions) leading to activation and signaling activity. a family of GPCRs originally found to be stimulated by purines, but now including receptors stimulated by a variety of nucleotides, including purines (ATP and ADP) and pyrimidines (UDP and UTP). a profile of the average amount of free energy (energy available to perform work) required to move a molecule along a specific path [reaction coordinates (RCs)]. MD analysis calculates changes in free energy associated with the probability of each possible conformational state, giving the average (mean) force on the substrate as its interactions change with different atoms along the RC. In the case of the ApoM–S1P PMF calculations, the steered MD analyses were performed using the umbrella sampling method followed by WHAM (weighted histogram analysis method). The umbrella method samples different potential changes in free energy between the substrate (S1P) and the chaperone (ApoM) along the RC, including sampling of energetically unfavorable states while biasing the impact of potential reactions to a biophysically relevant range. Application of WHAM to umbrella sampling data allows combining these biased samples to obtain an unbiased PMF. a biologically inactive molecule that is altered by an in vivo metabolism to a chemically distinct, biologically active form. a quantitative measure of the similarity between two superimposed atomic coordinates. For any structural model, a root mean square (RMS) value is determined for each atom, which gives the range of values obtained from the crystal structure for the coordinates in space of that particular atom. After optimal superimposition of two or more crystal structures, RMSD is calculated to determine the distance between all of the atoms of the reference structure (in this review, the structure for LPA1) versus the inquiry structures (S1P1 or LPA6). When both S1P1 and LPA6 were superimposed to LPA1, RMSDs were the smallest, meaning the LPA1 crystal structure was the most similar to both of the other receptors." @default.
• W2896089314 created "2018-10-26" @default.
• W2896089314 creator A5014799222 @default.
• W2896089314 creator A5054452370 @default.
• W2896089314 date "2018-11-01" @default.
• W2896089314 modified "2023-10-17" @default.
• W2896089314 title "‘Crystal’ Clear? Lysophospholipid Receptor Structure Insights and Controversies" @default.
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• W2896089314 doi "https://doi.org/10.1016/j.tips.2018.08.006" @default.
• W2896089314 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6201317" @default.
• W2896089314 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30343728" @default.
• W2896089314 hasPublicationYear "2018" @default.
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