PDBsum entry 3bum

Go to PDB code: 
protein ligands links
Ligase PDB id
Protein chain
304 a.a. *
Waters ×297
* Residue conservation analysis
PDB id:
Name: Ligase
Title: Crystal structure of c-cbl-tkb domain complexed with its binding motif in sprouty2
Structure: Portein sprouty homolog 2. Chain: a. Fragment: unp residues 49-61. Synonym: spry-2. Engineered: yes. E3 ubiquitin-protein ligase cbl. Chain: b. Fragment: c-cbl tkb domain, unp residues 25-351. Synonym: signal transduction protein cbl, proto-oncogenE C-
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: spry2. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: cbl, cbl2, rnf55.
2.00Å     R-factor:   0.224     R-free:   0.263
Authors: C.Ng,A.R.Jackson,P.J.Buschdorf,Q.Sun,R.G.Guy,J.Sivaraman
Key ref: C.Ng et al. (2008). Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates. EMBO J, 27, 804-816. PubMed id: 18273061 DOI: 10.1038/emboj.2008.18
03-Jan-08     Release date:   26-Feb-08    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P22681  (CBL_HUMAN) -  E3 ubiquitin-protein ligase CBL
906 a.a.
304 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     regulation of signaling   2 terms 
  Biochemical function     signal transducer activity     4 terms  


DOI no: 10.1038/emboj.2008.18 EMBO J 27:804-816 (2008)
PubMed id: 18273061  
Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.
C.Ng, R.A.Jackson, J.P.Buschdorf, Q.Sun, G.R.Guy, J.Sivaraman.
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.

Literature references that cite this PDB file's key reference

  PubMed id Reference
22266821 H.Dou, L.Buetow, A.Hock, G.J.Sibbet, K.H.Vousden, and D.T.Huang (2012).
Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl.
  Nat Struct Mol Biol, 19, 184-192.
PDB codes: 2y1m 2y1n 4a49 4a4b 4a4c
21332354 J.H.Hurley, and H.Stenmark (2011).
Molecular mechanisms of ubiquitin-dependent membrane traffic.
  Annu Rev Biophys, 40, 119-142.  
19864419 F.Edwin, K.Anderson, and T.B.Patel (2010).
HECT domain-containing E3 ubiquitin ligase Nedd4 interacts with and ubiquitinates Sprouty2.
  J Biol Chem, 285, 255-264.  
20877636 Q.Sun, R.A.Jackson, C.Ng, G.R.Guy, and J.Sivaraman (2010).
Additional serine/threonine phosphorylation reduces binding affinity but preserves interface topography of substrate proteins to the c-Cbl TKB domain.
  PLoS One, 5, e12819.
PDB codes: 3ob1 3ob2
20213668 R.J.Falconer, A.Penkova, I.Jelesarov, and B.M.Collins (2010).
Survey of the year 2008: applications of isothermal titration calorimetry.
  J Mol Recognit, 23, 395-413.  
19570949 F.Edwin, K.Anderson, C.Ying, and T.B.Patel (2009).
Intermolecular interactions of Sprouty proteins and their implications in development and disease.
  Mol Pharmacol, 76, 679-691.  
19635790 M.Shen, and A.Yen (2009).
c-Cbl tyrosine kinase-binding domain mutant G306E abolishes the interaction of c-Cbl with CD38 and fails to promote retinoic acid-induced cell differentiation and G0 arrest.
  J Biol Chem, 284, 25664-25677.  
19306898 R.L.Geahlen (2009).
Syk and pTyr'd: Signaling through the B cell antigen receptor.
  Biochim Biophys Acta, 1793, 1115-1127.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.