Structure of the complex between phosphorylated substrates and the SCF beta-TrCP ubiquitin ligase receptor: a combined NMR, molecular modeling, and docking approach.
The binding of phosphorylated peptides to the receptor plays a major role in many basic cellular processes in a variety of pathological states. Human beta-TrCP is a key component of a recently characterized E3 ubiquitin ligase complex that regulates protein degradation through the ubiquitin-dependent proteasome pathway. Docking studies were carried ... out to explore the structural requirements for the beta-TrCP substrates. Docking studies were performed on the bound conformation of the phosphorylated peptides determined by NMR, whereas the beta-TrCP structure was derived by X-ray from Protein Data Bank. After the docking calculation, during which the peptides were conformationally restrained, the complex presented herein was analyzed in terms of ligand-protein interactions and properties of contacting surfaces. The structural requirements for phosphorylated substrates in interaction with beta-TrCP were explored and compared with experimental data from TRNOESY and STD NMR results. The analysis revealed that the bend of the peptide structures, which is indispensable for beta-TrCP recognition, aligns two charged phosphate groups and a central hydrophobic group in a favorable arrangement that leads to the burial of the peptide surface in the binding cleft upon complexation. Through docking simulations, we have identified different specific binding pockets of beta-TrCP according to the ligand in interaction. These data should be valuable in the rational design of a ligand to be used in therapeutic approaches.
Mesh Terms:
Amino Acid Sequence, Catalytic Domain, Computer Simulation, Consensus Sequence, Crystallography, X-Ray, Humans, Ligands, Macromolecular Substances, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Peptides, Phosphorylation, SKP Cullin F-Box Protein Ligases, Sequence Homology, Amino Acid, Substrate Specificity, beta Catenin
Amino Acid Sequence, Catalytic Domain, Computer Simulation, Consensus Sequence, Crystallography, X-Ray, Humans, Ligands, Macromolecular Substances, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Peptides, Phosphorylation, SKP Cullin F-Box Protein Ligases, Sequence Homology, Amino Acid, Substrate Specificity, beta Catenin
J Chem Inf Model
Date: Dec. 01, 2008
PubMed ID: 19053519
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