PDBsum entry 2rol

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protein Protein-protein interface(s) links
Splicing/signaling protein PDB id
Protein chains
64 a.a. *
12 a.a. *
* Residue conservation analysis
PDB id:
Name: Splicing/signaling protein
Title: Structural basis of pxxdy motif recognition in sh3 binding
Structure: Epidermal growth factor receptor kinase substrate 8-like protein 1. Chain: a. Fragment: sh3 domain. Synonym: epidermal growth factor receptor pathway substrate 8-related protein 1, eps8-like protein 1. Engineered: yes. 12-meric peptide from t-cell surface glycoprotein cd3 epsilon chain.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: eps8l1. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: synthetic construct. This sequence occurs naturally in humans.
NMR struc: 20 models
Authors: O.Aitio,M.Hellman,T.Kesti,I.Kleino,O.Samuilova, H.Tossavainen,K.Paakkonen,K.Saksela,P.Permi
Key ref:
O.Aitio et al. (2008). Structural basis of PxxDY motif recognition in SH3 binding. J Mol Biol, 382, 167-178. PubMed id: 18644376 DOI: 10.1016/j.jmb.2008.07.008
02-Apr-08     Release date:   03-Mar-09    
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Protein chain
Pfam   ArchSchema ?
Q8TE68  (ES8L1_HUMAN) -  Epidermal growth factor receptor kinase substrate 8-like protein 1
723 a.a.
64 a.a.*
Protein chain
Pfam   ArchSchema ?
P07766  (CD3E_HUMAN) -  T-cell surface glycoprotein CD3 epsilon chain
207 a.a.
12 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)


DOI no: 10.1016/j.jmb.2008.07.008 J Mol Biol 382:167-178 (2008)
PubMed id: 18644376  
Structural basis of PxxDY motif recognition in SH3 binding.
O.Aitio, M.Hellman, T.Kesti, I.Kleino, O.Samuilova, K.Pääkkönen, H.Tossavainen, K.Saksela, P.Permi.
We have determined the solution structure of epidermal growth factor receptor pathway substrate 8 (Eps8) L1 Src homology 3 (SH3) domain in complex with the PPVPNPDYEPIR peptide from the CD3epsilon cytoplasmic tail. Our structure reveals the distinct structural features that account for the unusual specificity of the Eps8 family SH3 domains for ligands containing a PxxDY motif instead of canonical PxxP ligands. The CD3epsilon peptide binds Eps8L1 SH3 in a class II orientation, but neither adopts a polyproline II helical conformation nor engages the first proline-binding pocket of the SH3 ligand binding interface. Ile531 of Eps8L1 SH3, instead of Tyr or Phe residues typically found in this position in SH3 domains, renders this hydrophobic pocket smaller and nonoptimal for binding to conventional PxxP peptides. A positively charged arginine at position 512 in the n-Src loop of Eps8L1 SH3 plays a key role in PxxDY motif recognition by forming a salt bridge to D7 of the CD3epsilon peptide. In addition, our structural model suggests a hydrogen bond between the hydroxyl group of the aromatic ring of Y8 and the carboxyl group of E496, thus explaining the critical role of the PxxDY motif tyrosine residue in binding to Eps8 family SH3. These finding have direct implications also for understanding the atypical binding specificity of the amino-terminal SH3 of the Nck family proteins.
  Selected figure(s)  
Figure 3.
Fig. 3. Calorimetric titration of 12.5 μM Eps8L1 SH3 with 0.25 mM CD3ε peptide (PPVPNPDYEPIR) in 10 mM Tris–HCl buffer (pH 7.5), 50 mM NaCl, and 25 μM DTT at 25 °C.
Figure 5.
Fig. 5. Schematic presentation of (a) class I SH3 ligand binding (e.g., binding of the RPLPPLP peptide to Src SH3; 1QWF).^16 (b) Class II SH3 ligand binding (e.g., binding of TPQVPLR peptide from HIV-1 Nef to Fyn SH3; 1AVZ).^17 (c) Binding of CD3ε-derived peptide PPVPNPDY to Eps8L1 SH3 (2ROL) found in this study.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2008, 382, 167-178) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21227701 T.Kaneko, S.S.Sidhu, and S.S.Li (2011).
Evolving specificity from variability for protein interaction domains.
  Trends Biochem Sci, 36, 183-190.  
20038580 A.Yokota, K.Tsumoto, M.Shiroishi, T.Nakanishi, H.Kondo, and I.Kumagai (2010).
Contribution of asparagine residues to the stabilization of a proteinaceous antigen-antibody complex, HyHEL-10-hen egg white lysozyme.
  J Biol Chem, 285, 7686-7696.
PDB codes: 3a67 3a6b 3a6c
21098279 O.Aitio, M.Hellman, A.Kazlauskas, D.F.Vingadassalom, J.M.Leong, K.Saksela, and P.Permi (2010).
Recognition of tandem PxxP motifs as a unique Src homology 3-binding mode triggers pathogen-driven actin assembly.
  Proc Natl Acad Sci U S A, 107, 21743-21748.
PDB code: 2kxc
20418908 P.S.Liu, T.H.Jong, M.C.Maa, and T.H.Leu (2010).
The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation.
  Oncogene, 29, 3977-3989.  
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.  
19528316 W.Zhang, L.Wang, Y.Liu, J.Xu, G.Zhu, H.Cang, X.Li, M.Bartlam, K.Hensley, G.Li, Z.Rao, and X.C.Zhang (2009).
Structure of human lanthionine synthetase C-like protein 1 and its interaction with Eps8 and glutathione.
  Genes Dev, 23, 1387-1392.
PDB codes: 3e6u 3e73
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