1bbz
From Proteopedia
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CRYSTAL STRUCTURE OF THE ABL-SH3 DOMAIN COMPLEXED WITH A DESIGNED HIGH-AFFINITY PEPTIDE LIGAND: IMPLICATIONS FOR SH3-LIGAND INTERACTIONS
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Leukemia, Philadelphia chromosome-positive, resistant to imatinib OMIM:[189980]
About this Structure
1BBZ is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
Crystal structure of the abl-SH3 domain complexed with a designed high-affinity peptide ligand: implications for SH3-ligand interactions., Pisabarro MT, Serrano L, Wilmanns M, J Mol Biol. 1998 Aug 21;281(3):513-21. PMID:9698566
Page seeded by OCA on Fri Feb 15 15:31:43 2008
