Journal Article

PreJuSER-9746

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural studies of PI3K SH3 domain in complex with a peptide ligand: role of anchor residue in ligand binding

Batra-Safferling, R.FZJ* ; Granzin, J.FZJ* ; Moedder, S.FZJ* ; Hoffmann, S.FZJ* ; Willbold, D.FZJ*

2010
de Gruyter Berlin [u.a.]

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Please use a persistent id in citations: http://hdl.handle.net/2128/18353  doi:10.1515/BC.2010.003

Abstract: Src homology 3 (SH3) domains are mediators of protein-protein interactions. They comprise approximately 60 amino acid residues and are found in many intracellular signaling proteins. Here, we present the crystal structure of the SH3 domain from phosphatidylinositol 3-kinase (PI3K) in complex with the 12-residue proline-rich peptide PD1R (HSKRPLPPLPSL). The crystal structure of the PI3K SH3-PD1R complex at a resolution of 1.7 A reveals type I ligand orientation of the bound peptide with an extended conformation where the central portion forms a left-handed type II polyproline (PPII) helix. The overall structure of the SH3 domain shows minimal changes on ligand binding. In addition, we also attempted crystallization with another peptide ligand (PD1) where the residue at anchor position P(-3) is a tyrosine. The crystals obtained did not contain the PD1 ligand; instead, the ligand binding site is partially occupied by residues Arg18 and Trp55 from the symmetry-related PI3K SH3 molecule. Considering these crystal structures of PI3K SH3 together with published reports, we provide a comparative analysis of protein-ligand interactions that has helped us identify the individual residues which play an important role in defining target specificity.

Keyword(s): Amino Acid Sequence (MeSH) ; Binding Sites (MeSH) ; Crystallography, X-Ray (MeSH) ; Ligands (MeSH) ; Models, Molecular (MeSH) ; Molecular Sequence Data (MeSH) ; Oligopeptides: metabolism (MeSH) ; Peptides: chemistry (MeSH) ; Phosphatidylinositol 3-Kinases: chemistry (MeSH) ; Phosphatidylinositol 3-Kinases: metabolism (MeSH) ; Protein Binding (MeSH) ; src Homology Domains: physiology (MeSH) ; Ligands ; Oligopeptides ; Peptides ; histidyl-seryl-lysyl-arginyl-prolyl-leucyl-prolyl-prolyl-leucyl-prolyl-seryl-leucine ; polyproline ; Phosphatidylinositol 3-Kinases ; J ; phosphatidylinositol 3-kinase (auto) ; polyproline helix (auto) ; protein-ligand interaction (auto) ; Src homology 3 (auto) ; pi stacking (auto)

Note: The authors wish to thank Georg Buldt for continuous generous support. Furthermore, technical assistance by Esther Jonas and the beamline scientists at the ESRF (Grenoble, France) is acknowledged. We also thank Oliver Weiergraber for critical reading of the manuscript. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 575, B11) to D.W.

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Contributing Institute(s):

1. Strukturbiochemie (ISB-3)
2. Molekulare Biophysik (ISB-2)
3. Jülich Aachen Research Alliance - High-Performance Computing (JARA-HPC)

Research Program(s):

1. Funktion und Dysfunktion des Nervensystems (P33)
2. BioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung (P45)

Appears in the scientific report 2010

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