Carboxymethyl-phenylalanine as a Replacement for Phosphotyrosine in SH2 Domain Binding
| Autor: | Raj Betageri, John R. Proudfoot, Thomas C. Warren, Susan Lukas, Josephine Schembri-King, Liang Tong, Scott Jakes |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Models
Molecular Phosphotyrosine binding Protein Conformation Phenylalanine Molecular Conformation Crystal structure Crystallography X-Ray SH2 domain Closed conformation Biochemistry src Homology Domains Residue (chemistry) Side chain Humans Enzyme Inhibitors Phosphotyrosine Molecular Biology Binding Sites Molecular Structure Chemistry Cell Biology Crystallography Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Protein Binding Binding domain |
| Zdroj: | Journal of Biological Chemistry. 273:20238-20242 |
| ISSN: | 0021-9258 |
| Popis: | The crystal structure of human p56lck SH2 domain in complex with an inhibitor containing the singly chargedp-(carboxymethyl)phenylalanine residue (cmF) as a phosphotyrosine (Tyr(P) or pY) replacement has been determined at 1.8 A resolution. The binding mode of the acetyl-cmF-Glu-Glu-Ile (cmFEEI) inhibitor is very similar to that of the pYEEI inhibitor, confirming that the cmFEEI inhibitor has a similar mechanism of SH2 domain inhibition despite its significantly reduced potency. Observed conformational differences in the side chain of the cmF residue can be interpreted in terms of maintaining similar interactions with the SH2 domain as the Tyr(P) residue. The crystal structure of the free p56lck SH2 domain has been determined at 1.9 A resolution and shows an open conformation for the BC loop and an open phosphotyrosine binding pocket, in contrast to earlier studies on the srcSH2 domain that showed mostly closed conformation. The structural information presented here suggests that the carboxymethyl-phenylalanine residue may be a viable Tyr(P) replacement and represents an attractive starting point for the design and development of SH2 domain inhibitors with better pharmaceutical profiles. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|