Small nonphosphorylated Grb2-SH2 domain antagonists evaluated by surface plasmon resonance technology
| Autor: | Bih-Show Lou, Peng Li, Marc C. Nicklaus, Feng-Di T. Lung, Megan L. Peach, Meng-Chin Chong, Chiung-Wen Chang, Peter P. Roller, Chien-Chung Liou |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Molecular model Stereochemistry Protein domain Drug Evaluation Preclinical Molecular Conformation Biophysics Peptide SH2 domain Biochemistry src Homology Domains Biomaterials Structure-Activity Relationship Structure–activity relationship Phosphorylation Surface plasmon resonance Binding site chemistry.chemical_classification Fluorenes biology Chemistry Organic Chemistry General Medicine Surface Plasmon Resonance biology.protein GRB2 biological phenomena cell phenomena and immunity Peptides |
| Zdroj: | Biopolymers. 80:628-635 |
| ISSN: | 1097-0282 0006-3525 |
| DOI: | 10.1002/bip.20209 |
| Popis: | The growth factor receptor-binding protein-Src homology 2 (Grb2-SH2) domain plays an important role in the oncogenic Ras signal transduction pathway, which involves cell proliferation and differentiation. Therefore, the Grb2-SH2 domain has been chosen as our target for development of potential antiproliferative agents. Herein, we report the study of the inhibitory effects of small nonphosphorylated peptide analogs interacting with the Grb2-SH2 domain protein by surface plasmon resonance (SPR) technology. A set of 8 related peptide analogs were synthesized, purified, and characterized. Their inhibitory effects on Grb2-SH2 were evaluated by the SPR technology developed with the BIACORE X instrument. The lead peptide, Fmoc-Glu-Tyr-Aib-Asn-NH2 (Fmoc-E-Y-Aib-N; Fmoc: 9-fluorenylmethyoxycarbonyl; Aib=alpha-amino isobutyric acid) inhibited Grb2-SH2 domain function with an IC50 value of 8.7 microM. A molecular modeling study of the lead peptide indicated that the glutamate in the Fmoc peptide is ideally positioned to form a strong salt bridge to Arg 67 in the Grb2-SH2 domain, using both its backbone carbonyl and its acidic group. Residue Glu 89 in Grb2-SH2 flips inward to fill the binding site and partially replace the phosphate group as a hydrogen-bond acceptor. Results of these studies provide important information for further development of potent nonphosphorylated peptide inhibitors of the Grb2-SH2 domain. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text