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| Content Provider | Journal of Biological Chemistry (JBC) |
|---|---|
| Author | Benned-Jensen, Tau Smethurst, Christopher Holst, Peter J. Page, Kevin R. Sauls, Howard Sivertsen, Bjørn Schwartz, Thue W. Blanchard, Andy Jepras, Robert Rosenkilde, Mette M. |
| Abstract | The Epstein-Barr virus-induced receptor 2 (EBI2) is a constitutively active seven-transmembrane receptor, which was recently shown to orchestrate the positioning of B cells in the follicle. To date, no ligands, endogenously or synthetic, have been identified that modulate EBI2 activity. Here we describe an inverse agonist, GSK682753A, which selectively inhibited the constitutive activity of EBI2 with high potency and efficacy. In cAMP-response element-binding protein-based reporter and guanosine 5′-3-O-(thio)triphosphate (GTPγS) binding assays, the potency of this compound was 2.6–53.6 nm, and its inhibitory efficacy was 75%. In addition, we show that EBI2 constitutively activated extracellular signal-regulated kinase (ERK) in a pertussis toxin-insensitive manner. Intriguingly, GSK682753A inhibited ERK phosphorylation, GTPγS binding, and cAMP-response element-binding protein activation with similar potency. Overexpression of EBI2 profoundly potentiated antibody-stimulated ex vivo proliferation of murine B cells compared with WT cells, whereas this was equivalently reduced for EBI2-deficient B cells. Inhibition of EBI2 constitutive activity suppressed the proliferation in all cases. Importantly, the suppression was of much higher potency (32-fold) in WT or EBI2-overexpressing B cells compared with EBI2-deficient counterparts. Finally, we screened GSK682753A against an EBI2 mutant library to determine putative molecular binding determinants in EBI2. We identified Phe111 at position III:08/3.32 as being crucial for GSK682753A inverse agonism because Ala substitution resulted in a >500-fold decrease in IC50. In conclusion, we present the first ligand targeting EBI2. In turn, this molecule provides a useful tool for further characterization of EBI2 as well as serving as a potent lead compound. |
| Related Links | http://www.jbc.org/content/286/33/29292.abstract |
| Ending Page | 29302 |
| Starting Page | 29292 |
| Page Count | 11 |
| File Format | HTM / HTML PDF |
| ISSN | 00219258 |
| Journal | Journal of Biological Chemistry (JBC) |
| Issue Number | 33 |
| Volume Number | 286 |
| DOI | 10.1074/jbc.M110.196345 |
| e-ISSN | 1083351X |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology |
| Publisher Date | 2011-08-19 |
| Access Restriction | Open |
| Subject Keyword | ERK G Protein-coupled Receptors (GPCR) G Proteins Herpesvirus Receptor Structure-Function 7TM Receptor Constitutive Activity Inverse Agonism Membrane Biology |
| Alternative Title | Ligand Modulation of the Epstein-Barr Virus-induced Seven-transmembrane Receptor EBI2 |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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