3BUW
Crystal structure of c-Cbl-TKB domain complexed with its binding motif in Syk
Summary for 3BUW
Entry DOI | 10.2210/pdb3buw/pdb |
Related | 3BUM 3BUN 3BUO 3BUX |
Descriptor | 13-meric peptide from Tyrosine-protein kinase SYK, E3 ubiquitin-protein ligase CBL (3 entities in total) |
Functional Keywords | cbl, tkb, ligase, signal transduction, proto-oncogene, complex, alternative splicing, atp-binding, host-virus interaction, kinase, nucleotide-binding, phosphoprotein, polymorphism, sh2 domain, transferase, tyrosine-protein kinase, ubl conjugation, calcium, cytoplasm, metal-binding, ubl conjugation pathway, zinc, zinc-finger, ligase-signaling protein complex, ligase/signaling protein |
Biological source | Homo sapiens (human) More |
Cellular location | Cell membrane : P43405 Cytoplasm: P22681 |
Total number of polymer chains | 4 |
Total formula weight | 79471.31 |
Authors | Ng, C.,Jackson, R.A.,Buschdorf, J.P.,Sun, Q.,Guy, G.R.,Sivaraman, J. (deposition date: 2008-01-03, release date: 2008-02-26, Last modification date: 2024-11-13) |
Primary citation | Ng, C.,Jackson, R.A.,Buschdorf, J.P.,Sun, Q.,Guy, G.R.,Sivaraman, J. Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates Embo J., 27:804-816, 2008 Cited by PubMed Abstract: The c-Cbl tyrosine kinase binding domain (Cbl-TKB), essentially an 'embedded' SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate-binding affinity, we compared crystal structures of the Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors and validated the binding with point-mutational analyses using full-length proteins. An obligatory, intrapeptidyl H-bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orients the peptide into a positively charged pocket on c-Cbl. Surprisingly, c-Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H-bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c-Cbl; this may enable the selective sequestration of c-Cbl from other target proteins. PubMed: 18273061DOI: 10.1038/emboj.2008.18 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
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