PDBsum entry 2g6f

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Signaling protein PDB id
Protein chain
59 a.a. *
Waters ×309
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Crystal structure of the sh3 domain of betapix in complex with a high affinity peptide from pak2
Structure: Rho guanine nucleotide exchange factor 7. Chain: x. Fragment: sh3 domain(residues 10-63). Synonym: pak-interacting exchange factor beta, beta-pix. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: arhgef7, pak3bp, pixb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
0.92Å     R-factor:   0.185     R-free:   0.199
Authors: A.Hoelz
Key ref:
A.Hoelz et al. (2006). Crystal structure of the SH3 domain of betaPIX in complex with a high affinity peptide from PAK2. J Mol Biol, 358, 509-522. PubMed id: 16527308 DOI: 10.1016/j.jmb.2006.02.027
24-Feb-06     Release date:   11-Apr-06    
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Protein chain
Pfam   ArchSchema ?
O55043  (ARHG7_RAT) -  Rho guanine nucleotide exchange factor 7
646 a.a.
59 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)


DOI no: 10.1016/j.jmb.2006.02.027 J Mol Biol 358:509-522 (2006)
PubMed id: 16527308  
Crystal structure of the SH3 domain of betaPIX in complex with a high affinity peptide from PAK2.
A.Hoelz, J.M.Janz, S.D.Lawrie, B.Corwin, A.Lee, T.P.Sakmar.
The p21-activated kinases (PAKs) are important effector proteins of the small GTPases Cdc42 and Rac and control cytoskeletal rearrangements and cell proliferation. The direct interaction of PAKs with guanine nucleotide exchange factors from the PIX/Cool family, which is responsible for the localization of PAK kinases to focal complexes in the cell, is mediated by a 24-residue peptide segment in PAKs and an N-terminal src homology 3 (SH3) domain in PIX/Cool. The SH3-binding segment of PAK contains the atypical consensus-binding motif PxxxPR, which is required for unusually high affinity binding. In order to understand the structural basis for the high affinity and specificity of the PIX-PAK interaction, we solved crystal structures for the N-terminal SH3 domain of betaPIX and for the complex of the atypical binding segment of PAK2 with the N-terminal SH3 domain of betaPIX at 0.92 A and 1.3A resolution, respectively. The asymmetric unit of the crystal contains two SH3 domains and two peptide ligands. The bound peptide adopts a conformation that allows for intimate contacts with three grooves on the surface of the SH3 domain that lie between the n-Src and RT-loops. Most notably, the arginine residue of the PxxxPR motif forms a salt-bridge and is tightly coordinated by a number of residues in the SH3 domain. This arginine-specific interaction appears to be the key determinant for the high affinity binding of PAK peptides. Furthermore, C-terminal residues of the peptide engage in additional interactions with the surface of the RT-loop, which significantly increases binding specificity. Compared to a recent NMR structure of a similar complex, our crystal structure reveals an alternate binding mode. Finally, we compare our crystal structure with the recently published betaPIX/Cbl-b complex structure, and suggest the existence of a molecular switch.
  Selected figure(s)  
Figure 4.
Figure 4. The interface between the bPIX-SH3 domain and the PAK2-derived peptide. (a) Stereo view of the structure of the bPIX-SH3/PAK2 complex (red and yellow) which is superimposed on the structure of the bPIX-SH3 domain (gray). (b) The simulated-annealed 2F[o] -F[c] electron density map, sliced at 2.5 s, is shown for the PAK peptide (yellow stick representation). The C^a trace of the bPIX-SH3 domain is shown in red below the transparent van der Waals representation of the surface (gray). (c) Close-up view of the entire interface. PAK2 residues are labeled in yellow, and bPIX-SH3 domain residues are labeled in red. Residues in PAK2 that are essential for the interaction are labeled in orange.
Figure 6.
Figure 6. Comparison of the bPIX-SH3/PAK2 structure to other bPIX-SH3 structures. (a) Superposition of the crystal and NMR structures of the bPIX-SH3/PAK complex. Peptides are illustrated in stick representation. The bPIX-SH3 surface is shown in gray, and the peptides are colored according to the legend in (a). (b) Structure of the bPIX-SH3/Cbl-b complex shown in ribbon representation (PDB code 2AK5). The two bPIX-SH3 domains and the Cbl-b peptide are colored according to the legend in (b). (c) Superposition of the bPIX-SH3/PAK2 crystal structure with the bPIX-SH3 B/Cbl-b crystal structure. bPIX-SH3 A has been removed for clarity. Peptides are illustrated in stick representation. The peptides of the crystal structures are colored according to the legend in (c).
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2006, 358, 509-522) copyright 2006.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
18200608 O.Okhrimenko, and I.Jelesarov (2008).
A survey of the year 2006 literature on applications of isothermal titration calorimetry.
  J Mol Recognit, 21, 1.  
17652093 J.M.Janz, T.P.Sakmar, and K.C.Min (2007).
A novel interaction between atrophin-interacting protein 4 and beta-p21-activated kinase-interactive exchange factor is mediated by an SH3 domain.
  J Biol Chem, 282, 28893-28903.
PDB code: 2p4r
17020880 G.Moncalián, N.Cárdenes, Y.L.Deribe, M.Spínola-Amilibia, I.Dikic, and J.Bravo (2006).
Atypical polyproline recognition by the CMS N-terminal Src homology 3 domain.
  J Biol Chem, 281, 38845-38853.
PDB codes: 2j6f 2j6k 2j6o 2j7i
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