S1P1-selective in vivo-active agonists from high-throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate.
The essential role of the sphingosine 1-phosphate (S1P) receptor S1P(1) in regulating lymphocyte trafficking was demonstrated with the S1P(1)-selective nanomolar agonist, SEW2871. Despite its lack of charged headgroup, the tetraaromatic compound SEW2871 binds and activates S1P(1) through a combination of hydrophobic and ion-dipole interactions. Both S1P and SEW2871 activated ERK, Akt, and Rac signaling pathways and induced S1P(1) internalization and recycling, unlike FTY720-phosphate, which induces receptor degradation. Agonism with receptor recycling is sufficient for alteration of lymphocyte trafficking by S1P and SEW2871. S1P(1) modeling and mutagenesis studies revealed that residues binding the S1P headgroup are required for kinase activation by both S1P and SEW2871. Therefore, SEW2871 recapitulates the action of S1P in all the signaling pathways examined and overlaps in interactions with key headgroup binding receptor residues, presumably replacing salt-bridge interactions with ion-dipole interactions.
Jo
Euijung
E
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, ICND 118, La Jolla, CA 92037, USA.
Sanna
M Germana
MG
Gonzalez-Cabrera
Pedro J
PJ
Thangada
Shobha
S
Tigyi
Gabor
G
Osborne
Daniel A
DA
Hla
Timothy
T
Parrill
Abby L
AL
Rosen
Hugh
H
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008246:Lysophospholipids / Q000737:chemistry / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D015335:Molecular Probes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D008024:Ligands; D008246:Lysophospholipids; D015335:Molecular Probes; D010069:Oxadiazoles; D011518:Proto-Oncogene Proteins; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; C060506:sphingosine 1-phosphate; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020744:rac GTP-Binding Proteins; D013110:Sphingosine