PDBsum entry 1uti

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protein Protein-protein interface(s) links
Signaling protein regulator PDB id
Protein chains
57 a.a. *
16 a.a. *
Waters ×63
* Residue conservation analysis
PDB id:
Name: Signaling protein regulator
Title: Mona/gads sh3c in complex with hpk derived peptide
Structure: Grb2-related adaptor protein 2. Chain: a. Fragment: sh3c domain, residues 265-322. Synonym: gads protein, growth factor receptor binding protein, grb-2-like protein, grb2l, hematopoietic cell-associated adaptor protein grpl, grb-2-related monocytic adapter protein, monocytic adapter, mona, adapter protein grid. Engineered: yes.
Source: Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Organism_taxid: 10090
Biol. unit: Dimer (from PDB file)
1.5Å     R-factor:   0.208     R-free:   0.221
Authors: M.Lewitzky,M.Harkiolaki,M.C.Domart,S.M.Feller
Key ref:
M.Lewitzky et al. (2004). Mona/Gads SH3C binding to hematopoietic progenitor kinase 1 (HPK1) combines an atypical SH3 binding motif, R/KXXK, with a classical PXXP motif embedded in a polyproline type II (PPII) helix. J Biol Chem, 279, 28724-28732. PubMed id: 15100220 DOI: 10.1074/jbc.M402745200
09-Dec-03     Release date:   06-May-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O89100  (GRAP2_MOUSE) -  GRB2-related adaptor protein 2
322 a.a.
57 a.a.
Protein chain
Pfam   ArchSchema ?
P70218  (M4K1_MOUSE) -  Mitogen-activated protein kinase kinase kinase kinase 1
827 a.a.
16 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chain D: E.C.  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site


DOI no: 10.1074/jbc.M402745200 J Biol Chem 279:28724-28732 (2004)
PubMed id: 15100220  
Mona/Gads SH3C binding to hematopoietic progenitor kinase 1 (HPK1) combines an atypical SH3 binding motif, R/KXXK, with a classical PXXP motif embedded in a polyproline type II (PPII) helix.
M.Lewitzky, M.Harkiolaki, M.C.Domart, E.Y.Jones, S.M.Feller.
Hematopoietic progenitor kinase 1 (HPK1) is implicated in signaling downstream of the T cell receptor. Its non-catalytic, C-terminal half contains several prolinerich motifs, which have been shown to interact with different SH3 domain-containing adaptor proteins in vitro. One of these, Mona/Gads, was also shown to bind HPK1 in mouse T cells in vivo. The region of HPK1 that binds to the Mona/Gads C-terminal SH3 domain has been mapped and shows only very limited similarity to a recently identified high affinity binding motif in SLP-76, another T-cell adaptor. Using isothermal titration calorimetry and x-ray crystallography, the binding of the HPK1 motif to Mona/Gads SH3C has now been characterized in molecular detail. The results indicate that although charge interactions through an RXXK motif are essential for complex formation, a PXXP motif in HPK1 strongly complements binding. This unexpected binding mode therefore differs considerably from the previously described interaction of Mona/Gads SH3C with SLP-76. The crystal structure of the complex highlights the great versatility of SH3 domains, which allows interactions with very different proteins. This currently limits our ability to categorize SH3 binding properties by simple rules.
  Selected figure(s)  
Figure 2.
FIG. 2. Schematic representation of the Mona/Gads SH3C domain with the bound HPK1 peptide (P5). The depicted view looks down the -barrel arrangement of the SH3 domain. The PPII helix of P5 is highlighted in green, and the 3[10] helix is highlighted in orange.
Figure 5.
FIG. 5. Comparison of the Mona/Gads SH3-HPK1 peptide complex with other such structures. A, stereo view superposition of peptides from three different SH3-peptide complexes. SH3 domains are omitted for clarity. The HPK1 is colored (complex with Mona/Gads SH3C) in green, the Sos peptide (bound to Grb2 SH3N; 1GBQ [PDB] .pdb) is colored in orange, and the UBPY (USP8) peptide (in complex with Stam2 SH3; 1UJ0.pdb) is colored in yellow. Peptide orientation is identical in all three cases with N termini pointing up. B, detail of the interactions between the RXXK motif within the HPK1 peptide and Mona/Gads SH3C. C, the corresponding region from the Sos peptide-Grb2 SH3N complex (1GBQ [PDB] .pdb). For clarity, peptide residues are outlined by a light gray underlay.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 28724-28732) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19921743 C.Rubini, P.Ruzza, M.R.Spaller, G.Siligardi, R.Hussain, D.G.Udugamasooriya, M.Bellanda, S.Mammi, A.Borgogno, A.Calderan, L.Cesaro, A.M.Brunati, and A.Donella-Deana (2010).
Recognition of lysine-rich peptide ligands by murine cortactin SH3 domain: CD, ITC, and NMR studies.
  Biopolymers, 94, 298-306.  
19590096 E.J.Stollar, B.Garcia, P.A.Chong, A.Rath, H.Lin, J.D.Forman-Kay, and A.R.Davidson (2009).
Structural, functional, and bioinformatic studies demonstrate the crucial role of an extended peptide binding site for the SH3 domain of yeast Abp1p.
  J Biol Chem, 284, 26918-26927.
PDB code: 2rpn
19523899 M.Harkiolaki, T.Tsirka, M.Lewitzky, P.C.Simister, D.Joshi, L.E.Bird, E.Y.Jones, N.O'Reilly, and S.M.Feller (2009).
Distinct binding modes of two epitopes in Gab2 that interact with the SH3C domain of Grb2.
  Structure, 17, 809-822.
PDB codes: 2vvk 2vwf 2w0z 2w10
17993503 O.Moran, M.W.Roessle, R.A.Mariuzza, and N.Dimasi (2008).
Structural features of the full-length adaptor protein GADS in solution determined using small-angle X-ray scattering.
  Biophys J, 94, 1766-1772.  
17372910 B.Gril, M.Vidal, F.Assayag, M.F.Poupon, W.Q.Liu, and C.Garbay (2007).
Grb2-SH3 ligand inhibits the growth of HER2+ cancer cells and has antitumor effects in human cancer xenografts alone and in combination with docetaxel.
  Int J Cancer, 121, 407-415.  
17235283 B.T.Seet, D.M.Berry, J.S.Maltzman, J.Shabason, M.Raina, G.A.Koretzky, C.J.McGlade, and T.Pawson (2007).
Efficient T-cell receptor signaling requires a high-affinity interaction between the Gads C-SH3 domain and the SLP-76 RxxK motif.
  EMBO J, 26, 678-689.  
17010654 N.Dimasi (2007).
Crystal structure of the C-terminal SH3 domain of the adaptor protein GADS in complex with SLP-76 motif peptide reveals a unique SH3-SH3 interaction.
  Int J Biochem Cell Biol, 39, 109-123.
PDB code: 2d0n
16220545 A.Ababou, and J.E.Ladbury (2006).
Survey of the year 2004: literature on applications of isothermal titration calorimetry.
  J Mol Recognit, 19, 79-89.  
16277611 D.Shimazu, N.Yamamoto, A.Umino, S.Ishii, S.Sakurai, and T.Nishikawa (2006).
Inhibition of D-serine accumulation in the Xenopus oocyte by expression of the rat ortholog of human 3'-phosphoadenosine 5'-phosphosulfate transporter gene isolated from the neocortex as D-serine modulator-1.
  J Neurochem, 96, 30-42.  
16756506 R.P.Bhattacharyya, A.Reményi, B.J.Yeh, and W.A.Lim (2006).
Domains, motifs, and scaffolds: the role of modular interactions in the evolution and wiring of cell signaling circuits.
  Annu Rev Biochem, 75, 655-680.  
17130455 X.You, A.W.Nguyen, A.Jabaiah, M.A.Sheff, K.S.Thorn, and P.S.Daugherty (2006).
Intracellular protein interaction mapping with FRET hybrids.
  Proc Natl Acad Sci U S A, 103, 18458-18463.  
16158059 C.Reichman, K.Singh, Y.Liu, S.Singh, H.Li, J.E.Fajardo, A.Fiser, and R.B.Birge (2005).
Transactivation of Abl by the Crk II adapter protein requires a PNAY sequence in the Crk C-terminal SH3 domain.
  Oncogene, 24, 8187-8199.  
15770651 J.S.Boomer, and T.H.Tan (2005).
Functional interactions of HPK1 with adaptor proteins.
  J Cell Biochem, 95, 34-44.  
16061254 L.Deng, C.A.Velikovsky, C.P.Swaminathan, S.Cho, and R.A.Mariuzza (2005).
Structural basis for recognition of the T cell adaptor protein SLP-76 by the SH3 domain of phospholipase Cgamma1.
  J Mol Biol, 352, 1.
PDB codes: 1ywo 1ywp
  16508092 Q.Ye, V.K.Singh, J.D.Blonde, and Z.Jia (2005).
Crystallization and preliminary X-ray analysis of the GST-fused human Bri3 N-terminal domain.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 62-64.  
15743830 R.Arnold, I.M.Patzak, B.Neuhaus, S.Vancauwenbergh, A.Veillette, J.Van Lint, and F.Kiefer (2005).
Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase D1.
  Mol Cell Biol, 25, 2364-2383.  
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 code is shown on the right.