PDBsum entry 1bbz

Complex (transferase/peptide)

PDB id: 1bbz

Contents

Protein chains

58 a.a. *

11 a.a. *

Ligands

SO4 ×4

Waters ×269

* Residue conservation analysis

PDB id:

1bbz

Name:

Complex (transferase/peptide)

Title:

Crystal structure of the abl-sh3 domain complexed with a designed high-affinity peptide ligand: implications for sh3-ligand interactions

Structure:

Abl tyrosine kinase. Chain: a, c, e, g. Fragment: sh3 domain. Engineered: yes. Peptide p41. Chain: b, d, f, h. Engineered: yes

Source:

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

Biol. unit:

Dimer (from PQS)

Resolution:

1.65Å R-factor: 0.205 R-free: 0.266

Authors:

M.T.Pisabarro,L.Serrano,M.Wilmanns

Key ref:

M.T.Pisabarro et al. (1998). Crystal structure of the abl-SH3 domain complexed with a designed high-affinity peptide ligand: implications for SH3-ligand interactions. J Mol Biol, 281, 513-521. PubMed id: 9698566 DOI: 10.1006/jmbi.1998.1932

Date:

28-Apr-98 Release date: 25-Nov-98

Protein chains

P00519  (ABL1_HUMAN) -  Tyrosine-protein kinase ABL1 from Homo sapiens

Seq: 1130 a.a.

Struc: 58 a.a.

Protein chains

No UniProt id for this chain

Struc: 10 a.a.

Enzyme reactions

• Enzyme class: Chains A, C, E, G: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1006/jmbi.1998.1932

J Mol Biol 281:513-521 (1998)

PubMed id: 9698566

Crystal structure of the abl-SH3 domain complexed with a designed high-affinity peptide ligand: implications for SH3-ligand interactions.

M.T.Pisabarro, L.Serrano, M.Wilmanns.

ABSTRACT

The Abl-SH3 domain is implicated in negative regulation of the Abl kinase by mediating protein-protein interactions. High-affinity SH3 ligands could compete for these interactions and specifically activate the Abl kinase, providing control and a better understanding of the molecular interactions that underlie diseases where SH3 domains are involved. The p41 peptide (APSYSPPPPP) is a member of a group of peptide ligands designed to bind specifically the Abl-SH3 domain. It binds to Abl-SH3 with a Kd of 1.5 microM, whereas its affinity for the Fyn-SH3 domain is 273 microM. We have determined the crystal structure of the Abl-SH3 domain in complex with the high-affinity peptide ligand p41 at 1.6 A resolution. In the crystal structure, this peptide adopts a polyproline type II helix conformation through residue 5 to 10, and it binds in type I orientation to the Abl-SH3 domain. The tyrosine side-chain in position 4 of the peptide is hydrogen bonded to two residues in the RT-loop of the Abl-SH3 domain. The tight fit of this side-chain into the RT-loop pocket is enhanced by conformational adjustment of the main chain at position 5. The SH3 ligand peptides can be divided into two distinct parts. The N-terminal part binds to the SH3 domain in the region formed by the valley between the nSrc and RT-loops. It determines the specificity for different SH3 domains. The C-terminal part adopts a polyproline type II helix conformation. This binds to a well-conserved hydrophobic surface of the SH3 domain. Analysis of two "half"-peptides, corresponding to these ligand parts, shows that both are essential components for strong binding to the SH3 domains. The crystal structure of the Abl-SH3:p41 complex explains the high affinity and specificity of the p41 peptide towards the Abl-SH3 domain, and reveals principles that will be exploited for future design of small, high-affinity ligands to interfere efficiently with the in vivo regulation of Abl kinase activity.

Selected figure(s)

Figure 3.
Figure 3. 2Fo - Fc electron density map using phases of the refined complex. The map shows residues of the Abl-SH3 RT-loop that interact with the tyrosine residue at position 4 of the p41 peptide. Hydrogen bonds between protein and peptide are indicated as broken lines. The color-coding is as in Figure 2.

Figure 4.
Figure 4. Superposition of the Abl-SH3:p41 (orange) and Abl-SH3:3BP1 (blue) complexes. The SH3 domain is rep- resented as a ribbon, and critical residues for the bind- ing are displayed as ball and sticks. Hydrogen bonds are indicated as broken lines.

The above figures are reprinted by permission from Elsevier: J Mol Biol (1998, 281, 513-521) copyright 1998.

Figures were selected by an automated process.