PDBsum entry 1gcq

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protein ligands Protein-protein interface(s) links
Signaling protein/signaling protein PDB id
Protein chains
56 a.a. *
69 a.a. *
Waters ×189
* Residue conservation analysis
PDB id:
Name: Signaling protein/signaling protein
Title: Crystal structure of vav and grb2 sh3 domains
Structure: Growth factor receptor-bound protein 2. Chain: a, b. Fragment: c-terminal sh3 domain. Engineered: yes. Vav proto-oncogene. Chain: c. Fragment: n-terminal sh3 domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Mus musculus. House mouse. Organism_taxid: 10090. Cell_line: hematopoietic cells.
Biol. unit: Trimer (from PQS)
1.68Å     R-factor:   0.201     R-free:   0.235
Authors: M.Nishida,K.Nagata,Y.Hachimori,K.Ogura,F.Inagaki
Key ref:
M.Nishida et al. (2001). Novel recognition mode between Vav and Grb2 SH3 domains. EMBO J, 20, 2995-3007. PubMed id: 11406576 DOI: 10.1093/emboj/20.12.2995
08-Aug-00     Release date:   08-Aug-01    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P62993  (GRB2_HUMAN) -  Growth factor receptor-bound protein 2
217 a.a.
56 a.a.*
Protein chain
Pfam   ArchSchema ?
P27870  (VAV_MOUSE) -  Proto-oncogene vav
845 a.a.
69 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     small GTPase mediated signal transduction   1 term 


DOI no: 10.1093/emboj/20.12.2995 EMBO J 20:2995-3007 (2001)
PubMed id: 11406576  
Novel recognition mode between Vav and Grb2 SH3 domains.
M.Nishida, K.Nagata, Y.Hachimori, M.Horiuchi, K.Ogura, V.Mandiyan, J.Schlessinger, F.Inagaki.
Vav is a guanine nucleotide exchange factor for the Rho/Rac family that is expressed exclusively in hematopoietic cells. Growth factor receptor-bound protein 2 (Grb2) has been proposed to play important roles in the membrane localization and activation of Vav through dimerization of its C-terminal Src-homology 3 (SH3) domain (GrbS) and the N-terminal SH3 domain of Vav (VavS). The crystal structure of VavS complexed with GrbS has been solved. VavS is distinct from other SH3 domain proteins in that its binding site for proline-rich peptides is blocked by its own RT loop. One of the ends of the VavS beta-barrel forms a concave hydrophobic surface. The GrbS components make a contiguous complementary interface with the VavS surface. The binding site of GrbS for VavS partially overlaps with the canonical binding site for proline-rich peptides, but is definitely different. Mutations at the interface caused a decrease in the binding affinity of VavS for GrbS by 4- to 40-fold. The structure reveals how GrbS discriminates VavS specifically from other signaling molecules without binding to the proline-rich motif.
  Selected figure(s)  
Figure 3.
Figure 3 Tetraproline region and PPII helix-binding site of VavS. (A) The ribbon diagram for VavS in the complex crystal is shown with the tetraproline region close to the viewer. Residues 606 -612 encompassing the tetraproline region, and the residues interacting with them or expected to form the PPII helix-binding site are drawn as rods in red and blue, respectively. (B) The molecular surface of VavS by GRASP (Nicholls et al., 1991) is colored according to the local electrostatic potential, with colors ranging from blue (positive) to red (negative) through white (neutral). The tetraproline region is drawn as red rods, and the peptide ligand for the Sem-5 SH3 domain is superposed on the molecular surface (yellow rods). The expected binding sites of VavS for the proline-rich peptide are labeled with their identification codes.
Figure 5.
Figure 5 Schematic views of the VavS -GrbS A interface. (A) The molecular surface of VavS is shown as a transparent worm with the VavS -GrbSA interface close to the viewer. The VavS residues at the interface are drawn as green rods. For clarity, some residues that interact minimally with GrbS A are omitted (His634, Cys652, Val655 and His 656). The polypeptide backbone of the N-terminal tail derived from the expression vector is traced as a dotted line in white. (B) The side chains (rods) and polypeptide backbone (magenta tubes) of the GrbS residues at the interface are superposed on VavS. (C) The molecular surfaces of the Abl (left) (Musacchio et al., 1994) and Hck (right) (Sicheri et al., 1997) SH3 domains are shown in the same orientation as that of VavS in (A) and (B). Only the regions corresponding to residues 595 -659 of VavS are shown.
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2001, 20, 2995-3007) copyright 2001.  
  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.  
21129722 A.Pearlman, J.Loke, C.Le Caignec, S.White, L.Chin, A.Friedman, N.Warr, J.Willan, D.Brauer, C.Farmer, E.Brooks, C.Oddoux, B.Riley, S.Shajahan, G.Camerino, T.Homfray, A.H.Crosby, J.Couper, A.David, A.Greenfield, A.Sinclair, and H.Ostrer (2010).
Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination.
  Am J Hum Genet, 87, 898-904.  
20208353 K.Nagata (2010).
Studies of the structure-activity relationships of peptides and proteins involved in growth and development based on their three-dimensional structures.
  Biosci Biotechnol Biochem, 74, 462-470.  
20562827 M.Barda-Saad, N.Shirasu, M.H.Pauker, N.Hassan, O.Perl, A.Balbo, H.Yamaguchi, J.C.Houtman, E.Appella, P.Schuck, and L.E.Samelson (2010).
Cooperative interactions at the SLP-76 complex are critical for actin polymerization.
  EMBO J, 29, 2315-2328.  
19909361 K.Neumann, T.Oellerich, H.Urlaub, and J.Wienands (2009).
The B-lymphoid Grb2 interaction code.
  Immunol Rev, 232, 135-149.  
17923698 E.Giurisato, M.Cella, T.Takai, T.Kurosaki, Y.Feng, G.D.Longmore, M.Colonna, and A.S.Shaw (2007).
Phosphatidylinositol 3-kinase activation is required to form the NKG2D immunological synapse.
  Mol Cell Biol, 27, 8583-8599.  
18021454 J.Noirel, and T.Simonson (2007).
Neutral evolution of protein-protein interactions: a computational study using simple models.
  BMC Struct Biol, 7, 79.  
16899489 A.D.van Dijk, and A.M.Bonvin (2006).
Solvated docking: introducing water into the modelling of biomolecular complexes.
  Bioinformatics, 22, 2340-2347.  
17050525 A.V.Miletic, K.Sakata-Sogawa, M.Hiroshima, M.J.Hamann, T.S.Gomez, N.Ota, T.Kloeppel, O.Kanagawa, M.Tokunaga, D.D.Billadeau, and W.Swat (2006).
Vav1 acidic region tyrosine 174 is required for the formation of T cell receptor-induced microclusters and is essential in T cell development and activation.
  J Biol Chem, 281, 38257-38265.  
16584884 H.Alonso, and J.E.Gready (2006).
Integron-sequestered dihydrofolate reductase: a recently redeployed enzyme.
  Trends Microbiol, 14, 236-242.  
16582911 J.L.Upshaw, L.N.Arneson, R.A.Schoon, C.J.Dick, D.D.Billadeau, and P.J.Leibson (2006).
NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells.
  Nat Immunol, 7, 524-532.  
16709244 J.L.Wilsbacher, S.L.Moores, and J.S.Brugge (2006).
An active form of Vav1 induces migration of mammary epithelial cells by stimulating secretion of an epidermal growth factor receptor ligand.
  Cell Commun Signal, 4, 5.  
16644733 M.R.Schiller, K.Chakrabarti, G.F.King, N.I.Schiller, B.A.Eipper, and M.W.Maciejewski (2006).
Regulation of RhoGEF activity by intramolecular and intermolecular SH3 domain interactions.
  J Biol Chem, 281, 18774-18786.
PDB code: 1u3o
16456539 O.Kristensen, S.Guenat, I.Dar, N.Allaman-Pillet, A.Abderrahmani, M.Ferdaoussi, R.Roduit, F.Maurer, J.S.Beckmann, J.S.Kastrup, M.Gajhede, and C.Bonny (2006).
A unique set of SH3-SH3 interactions controls IB1 homodimerization.
  EMBO J, 25, 785-797.
PDB codes: 2fpd 2fpe 2fpf
15708849 C.Charvet, A.J.Canonigo, D.D.Billadeau, and A.Altman (2005).
Membrane localization and function of Vav3 in T cells depend on its association with the adapter SLP-76.
  J Biol Chem, 280, 15289-15299.  
15200958 J.A.Marles, S.Dahesh, J.Haynes, B.J.Andrews, and A.R.Davidson (2004).
Protein-protein interaction affinity plays a crucial role in controlling the Sho1p-mediated signal transduction pathway in yeast.
  Mol Cell, 14, 813-823.  
12876557 C.E.Rudd, and H.Schneider (2003).
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  Nat Rev Immunol, 3, 544-556.  
12635144 I.Hornstein, E.Pikarsky, M.Groysman, G.Amir, N.Peylan-Ramu, and S.Katzav (2003).
The haematopoietic specific signal transducer Vav1 is expressed in a subset of human neuroblastomas.
  J Pathol, 199, 526-533.  
14579354 J.Mintseris, and Z.Weng (2003).
Atomic contact vectors in protein-protein recognition.
  Proteins, 53, 629-639.  
12773374 M.Harkiolaki, M.Lewitzky, R.J.Gilbert, E.Y.Jones, R.P.Bourette, G.Mouchiroud, H.Sondermann, I.Moarefi, and S.M.Feller (2003).
Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76.
  EMBO J, 22, 2571-2582.
PDB code: 1oeb
12818159 S.Johmura, M.Oh-hora, K.Inabe, Y.Nishikawa, K.Hayashi, E.Vigorito, D.Kitamura, M.Turner, K.Shingu, M.Hikida, and T.Kurosaki (2003).
Regulation of Vav localization in membrane rafts by adaptor molecules Grb2 and BLNK.
  Immunity, 18, 777-787.  
12688310 S.M.Feller, G.Tuchscherer, and J.Voss (2003).
High affinity molecules disrupting GRB2 protein complexes as a therapeutic strategy for chronic myelogenous leukaemia.
  Leuk Lymphoma, 44, 411-427.  
12640133 S.Yamasaki, K.Nishida, M.Sakuma, D.Berry, C.J.McGlade, T.Hirano, and T.Saito (2003).
Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells.
  Mol Cell Biol, 23, 2515-2529.  
13129930 T.Kaneko, T.Kumasaka, T.Ganbe, T.Sato, K.Miyazawa, N.Kitamura, and N.Tanaka (2003).
Structural insight into modest binding of a non-PXXP ligand to the signal transducing adaptor molecule-2 Src homology 3 domain.
  J Biol Chem, 278, 48162-48168.
PDB code: 1uj0
12670394 V.L.Tybulewicz, L.Ardouin, A.Prisco, and L.F.Reynolds (2003).
Vav1: a key signal transducer downstream of the TCR.
  Immunol Rev, 192, 42-52.  
12453410 A.Douangamath, F.V.Filipp, A.T.Klein, P.Barnett, P.Zou, T.Voorn-Brouwer, M.C.Vega, O.M.Mayans, M.Sattler, B.Distel, and M.Wilmanns (2002).
Topography for independent binding of alpha-helical and PPII-helical ligands to a peroxisomal SH3 domain.
  Mol Cell, 10, 1007-1017.
PDB codes: 1jqq 1n5z
11711548 H.Delbrück, G.Ziegelin, E.Lanka, and U.Heinemann (2002).
An Src homology 3-like domain is responsible for dimerization of the repressor protein KorB encoded by the promiscuous IncP plasmid RP4.
  J Biol Chem, 277, 4191-4198.
PDB codes: 1igq 1igu
12228230 J.L.Zugaza, M.A.López-Lago, M.J.Caloca, M.Dosil, N.Movilla, and X.R.Bustelo (2002).
Structural determinants for the biological activity of Vav proteins.
  J Biol Chem, 277, 45377-45392.  
12169629 K.Kami, R.Takeya, H.Sumimoto, and D.Kohda (2002).
Diverse recognition of non-PxxP peptide ligands by the SH3 domains from p67(phox), Grb2 and Pex13p.
  EMBO J, 21, 4268-4276.
PDB code: 1k4u
12094222 M.Turner, and D.D.Billadeau (2002).
VAV proteins as signal integrators for multi-subunit immune-recognition receptors.
  Nat Rev Immunol, 2, 476-486.  
11884391 P.Sachdev, L.Zeng, and L.H.Wang (2002).
Distinct role of phosphatidylinositol 3-kinase and Rho family GTPases in Vav3-induced cell transformation, cell motility, and morphological changes.
  J Biol Chem, 277, 17638-17648.  
12501157 R.L.Rich, and D.G.Myszka (2002).
Survey of the year 2001 commercial optical biosensor literature.
  J Mol Recognit, 15, 352-376.  
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.