PDBsum entry 1wyx

Cell adhesion

PDB id: 1wyx

Contents

Protein chains

68 a.a. *

Ligands

EDO

Metals

_MG

Waters ×165

* Residue conservation analysis

PDB id:

1wyx

Name:

Cell adhesion

Title:

The crystal structure of the p130cas sh3 domain at 1.1 a resolution

Structure:

Crk-associated substrate. Chain: a, b. Fragment: sh3 domain. Synonym: crk-associated tyrosine kinase substrate p130cas, cas, p130cas, breast cancer anti-estrogen resistance 1 protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.14Å R-factor: 0.177 R-free: 0.191

Authors:

M.Wisniewska,B.Bossenmaier,G.Georges,F.Hesse,M.Dangl,K.P.Kuenkele, I.Ioannidis,R.Huber,R.A.Engh

Key ref:

M.Wisniewska et al. (2005). The 1.1 A resolution crystal structure of the p130cas SH3 domain and ramifications for ligand selectivity. J Mol Biol, 347, 1005-1014. PubMed id: 15784259 DOI: 10.1016/j.jmb.2005.02.017

Date:

17-Feb-05 Release date: 26-Apr-05

Protein chains

P56945  (BCAR1_HUMAN) -  Breast cancer anti-estrogen resistance protein 1 from Homo sapiens

Seq: 870 a.a.

Struc: 68 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1016/j.jmb.2005.02.017

J Mol Biol 347:1005-1014 (2005)

PubMed id: 15784259

The 1.1 A resolution crystal structure of the p130cas SH3 domain and ramifications for ligand selectivity.

M.Wisniewska, B.Bossenmaier, G.Georges, F.Hesse, M.Dangl, K.P.Künkele, I.Ioannidis, R.Huber, R.A.Engh.

ABSTRACT

The Crk-associated tyrosine kinase substrate p130cas (CAS) is a docking protein containing an SH3 domain near its N terminus, followed by a short proline-rich segment, a large central substrate domain composed of 15 repeats of the four amino acid sequence YxxP, a serine-rich region and a carboxy-terminal domain, which possesses consensus binding sites for the SH2 and SH3 domains of Src (YDYV and RPLPSPP, respectively). The SH3 domain of CAS mediates its interaction with several proteins involved in signaling pathways such as focal adhesion kinase (FAK), tyrosine phosphatases PTP1B and PTP-PEST, and the guanine nucleotide exchange factor C3G. As a homolog of the corresponding Src docking domain, the CAS SH3 domain binds to proline-rich sequences (PxxP) of its interacting partners that can adopt a polyproline type II helix. We have determined a high-resolution X-ray structure of the recombinant human CAS SH3 domain. The domain, residues 1-69, crystallized in two related space groups, P2(1) and C222(1), that provided diffraction data to 1.1 A and 2.1 A, respectively. The crystal structure shows, in addition to the conserved SH3 domain architecture, the way in which the CAS characteristic amino acids form an atypically charged ligand-binding surface. This arrangement provides a rationale for the unusual ligand recognition motif exhibited by the CAS SH3 domain. The structure enables modelling of the docking interactions to its ligands, for example from focal adhesion kinase, and supports structure-based drug design of inhibitors of the CAS-FAK interaction.

Selected figure(s)

Figure 5.
Figure 5. The CA traces of the superposed SH3 domains of CAS (green, cyan and blue indicate the monomer, chain A and B, respectively), PI3K (orange) and a-spectrin (red).

Figure 7.
Figure 7. Model of the FAK peptide bound to the CAS SH3 domain. (a) Peptide residues are shown in green and numbered from 1 to 9. Residues that are involved in ligand binding are shown in ball and stick representation (the highly conserved amino acid residues are in cyan). (b) The CA traces of the superposed CAS SH3-FAK peptide complex (magenta) and C-Src SH3-App12 complex (cyan) (1QWE).31 (c) Interface of the CAS SH3-peptide complex interactions. SH3 domain is shown as a surface plot (residues in red, negatively charged; blue, positively charged; white, neutral), FAK peptide is shown in green.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 347, 1005-1014) copyright 2005.

Figures were selected by an automated process.