Small-molecule ligands of GD2 ganglioside, designed from NMR studies, exhibit induced-fit binding and bioactivity Journal Article
| Authors: | Tong, W.; Gagnon, M.; Sprules, T.; Gilbert, M.; Chowdhury, S.; Meerovitch, K.; Hansford, K.; Purisima, E. O.; Blankenship, J. W.; Cheung, N. K. V.; Gehring, K.; Lubell, W. D.; Saragovi, H. U. |
| Article Title: | Small-molecule ligands of GD2 ganglioside, designed from NMR studies, exhibit induced-fit binding and bioactivity |
| Abstract: | Ganglioside GD2 is a cell surface glycosphingolipid. Targeting of GD2, i.e., by anti-GD2 mAb 3F8, is used clinically for cancer diagnosis, prognosis, and therapy. Here, the conformations of free GD2, and of GD2 bound to mAb 3F8, were resolved by saturation transfer difference NMR and molecular modeling. Then, three small-molecule cyclic peptide ligands that bind to GD2 selectively were designed. Transferred nuclear Overhauser enhancement of the GD2-bound conformation of the peptide ligands showed an induced-fit binding mechanism. The mAb 3F8 and the peptidic GD2 ligands mediate similar biological functions in cell-based assays of calcium fluxes and src activation. Thus, small molecules can selectively and functionally interact with a sugar head group. This work furthers the concept of rationally designing ligands for carbohydrate targets, and may be expanded to other clinically relevant gangliosides. © 2010 Elsevier Ltd. All rights reserved. |
| Keywords: | metabolism; calcium; protein tyrosine kinase; enzyme linked immunosorbent assay; monoclonal antibody; immunology; antibodies, monoclonal; chembio; chemistry; epitope mapping; ligand; magnetic resonance spectroscopy; nuclear magnetic resonance spectroscopy; ligands; binding site; computer simulation; models, molecular; binding sites; chemical structure; enzyme-linked immunosorbent assay; src-family kinases; synthesis; peptides, cyclic; cyclopeptide; gangliosides; ganglioside; ganglioside, gd2 |
| Journal Title: | Chemistry and Biology |
| Volume: | 17 |
| Issue: | 2 |
| ISSN: | 1074-5521 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2010-02-26 |
| Start Page: | 183 |
| End Page: | 194 |
| Language: | English |
| DOI: | 10.1016/j.chembiol.2010.01.012 |
| PUBMED: | 20189108 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: CBOLE" - "Source: Scopus" |
