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

References listed in PDB file

Key reference

Title

Crystal structure of the abl-Sh3 domain complexed with a designed high-Affinity peptide ligand: implications for sh3-Ligand interactions.

Authors

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

Ref.

J Mol Biol, 1998, 281, 513-521. [DOI no: 10.1006/jmbi.1998.1932]

PubMed id

9698566

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.



	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.