Crystal Structure of a Lipid G protein-Coupled Receptor

By M. Hanson, Christopher B. Roth, E. Jo, Mark T. Griffith, F. Scott, Greg J. Reinhart, H. Desale, B. Clemons, Stuart M. Cahalan, S. Schuerer and 5 more. Science, 2012

689 citations recorded by the source corpus.

A Lipid-Sensing GPCR Sphingosine 1-phosphate (S1P) is a sphingolipid that binds to the G protein–coupled receptor subtype 1 (S1P1) to activate signaling pathways involved in regulation of the vascular and immune systems. Hanson et al. (p. 851) determined the crystal structure of S1PR in complex with an antagonist sphingolipid mimic. Ligand access to the receptor from the extracellular milieu is occluded, and a gap between helices I and VII may provide ligand access from within the membrane. The structural information, together with mutagenesis and structure activity relationship data, provides insight into the molecular recognition events that modulate signaling. A channel in a lipid-dependent G protein–coupled receptor allows a ligand to access its binding site from within the plasma membrane. The lyso-phospholipid sphingosine 1-phosphate modulates lymphocyte trafficking, endothelial development and integrity, heart rate, and vascular tone and maturation by activating G protein–coupled sphingosine 1-phosphate receptors. Here, we present the crystal structure of the sphingosine 1-phosphate receptor 1 fused to T4-lysozyme (S1P1-T4L) in complex with an antagonist sphingolipid mimic. Extracellular access to the binding pocket is occluded by the amino terminus and extracellular loops of the receptor. Access is gained by ligands entering laterally between helices I and VII within the transmembrane region of the receptor. This structure, along with mutagenesis, agonist structure-activity relationship data, and modeling, provides a detailed view of the molecular recognition and requirement for hydrophobic volume that activates S1P1, resulting in the modulation of immune and stromal cell responses.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8712cea6b7ca35a99e2f60f9b827f8e3a329a586

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Citations in the corpus

Ligand–receptor interaction platforms and their applications for drug discovery (2012, background): “These include rhodopsin [124], b2-adrenergic receptor [125], b1-adrenergic receptor [126], adenosine A2A receptor [127], CXCR4 chemokine receptor [128], dopamine D3 receptor [129], histamine H1 receptor [130], sphingosine 1-phosphate S1P1 receptor [131], muscarinic M3 acetylcholine receptor [132], m”
GPCR Network: a large-scale collaboration on GPCR structure and function (2012, background): “26) , κ-type opioid receptor 22 and NOP 17 .”
GPCR-SSFE 2.0—a fragment-based molecular modeling web tool for Class A G-protein coupled receptors (2017, background): “the Sphingosine 1-phosphate receptor 1 (alanine in position 5×50; PDB ID: 3V2W (34)), the P2Y12 receptor (asparagine in position 5×50; PDB ID: 4NTJ (35)) and the LysophosphatidicAcid-Receptor 1 (threonine in position 5×50, LPAR1, PDB ID: 4Z34 (36)).”
Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition (2021, background): “Despite the urgent need, the development of specific agonists that selectively target S1PRs is greatly hindered by the high sequence homology among S1PRs and the lack of structural information on active S1PRs bound to agonists.(19) Only the crystal structure of inactive S1PR1 bound with an antagonis”
GOMoDo: A GPCRs Online Modeling and Docking Webserver (2013, background): “[48], UniProt ID: P21453), with a sequence identity of 22.”
Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors (2013, neutral): “…b 1-adrenergic [15], b 2-adrenergic [16], A2A adenosine [17], CXCR4 chemokine [18], dopamine D3 [19], histamine H1 [20], S1P1 sphingosine 1-phosphate [21], M2 muscarinc acetylcholine [22], M3 muscarinic acetylecholine [23], mu-opioid [24], kappa-opioid [25], N/OFQ opioid [26] and delta-opioid [27].”
GPCRDB: an information system for G protein-coupled receptors (2013, background): “The S1P lipid receptor [red, PDBid=3v2y (12)] does not have a-bulges in helix V and is provided as a reference.”
Structure-based drug screening for G-protein-coupled receptors. (2012, background): “Since the initial crystal structures of the β2AR[11] and the β1AR[12], the number of published GPCRs which have yielded to crystallography has grown to ten and includes the adenosine A2A receptor[13], the D3 dopamine receptor[14], the CXCR4 receptor [15], the histamine H1 receptor, [16], the sphingo”