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Changes in the NMR-derived motional parameters of the insulin receptor substrate 1 phosphotyrosine binding domain upon binding to an interleukin 4 receptor phosphopeptide.
Olejniczak ET, Zhou MM, Fesik SW
(1997) Biochemistry 36: 4118-24
MeSH Terms: Amino Acid Sequence, Antigens, CD, Binding Sites, Chemical Phenomena, Chemistry, Physical, Insulin Receptor Substrate Proteins, Kinetics, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Phosphopeptides, Phosphoproteins, Phosphotyrosine, Protein Binding, Protein Conformation, Receptors, Interleukin, Receptors, Interleukin-4, Recombinant Proteins, Type C Phospholipases, src Homology Domains
Show Abstract · Added March 5, 2014
Proteins recognize ligands by forming specific intermolecular interactions that often involve solvent exposed residues. Changes in the motional properties of these residues upon binding can affect the conformational entropy of the system and thus are related to the energetics of binding. The role that dynamics plays in ligand recognition can be investigated by comparing the motional properties of a free and ligated protein. NMR relaxation studies are well suited for examining changes in dynamics, especially for motions on a nanosecond to picosecond time scale. Recently, we determined the solution structure of the phosphotyrosine binding (PTB) domain of the insulin receptor substrate (IRS-1) complexed to a tyrosine-phosphorylated peptide derived from the interleukin 4 (IL-4) receptor [Zhou et al., (1996) Nat. Struct. Biol. 3, 388-393]. The peptide binds tightly to the protein in a surface exposed pocket, resulting in the partial burial of many protein residues. Using NMR relaxation studies, the dynamics of the backbone nitrogens of IRS-1 PTB domain were studied in both the free protein and the protein when complexed to the IL-4 receptor phosphopeptide. The backbone nitrogens of many residues that make important contacts to the ligand are motionally restricted in the free and complexed protein. Additional residues become motionally restricted only after ligand binding, including several residues that do not make any direct contacts with the ligand. These observed changes in the dynamics are compared to structural features of the complex.
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21 MeSH Terms
Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 PTB domain.
Zhou MM, Huang B, Olejniczak ET, Meadows RP, Shuker SB, Miyazaki M, TrĂ¼b T, Shoelson SE, Fesik SW
(1996) Nat Struct Biol 3: 388-93
MeSH Terms: Amino Acid Sequence, Antigens, CD, Binding Sites, Insulin Receptor Substrate Proteins, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphopeptides, Phosphoproteins, Phosphotyrosine, Protein Conformation, Protein Structure, Tertiary, Receptors, Interleukin, Receptors, Interleukin-4, Sequence Alignment
Show Abstract · Added March 5, 2014
We present the NMR structure of the PTB domain of insulin receptor substrate-1 (IRS-1) complexed to a tyrosine-phosphorylated peptide derived from the IL-4 receptor. Despite the lack of sequence homology and different binding specificity, the overall fold of the protein is similar to that of the Shc PTB domain and closely resembles that of PH domains. However, the PTB domain of IRS-1 is smaller than that of Shc (110 versus 170 residues) and binds to phosphopeptides in a distinct manner. We explain the phosphopeptide binding specificity based on the structure of the complex and results of site-directed mutagenesis experiments.
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16 MeSH Terms