ABSTRACT
As a way to develop a neuroprotective agent for the JNK3-JIP1-binding site, peptidomimetics of JIP-1 as JNK3 allosteric regulators have been examined. The study consisted of in silico scaffold hopping, molecular docking, solution and solid-phase peptide syntheses, and Kd measurements using surface plasmon resonance. As a peptidomimetic of JIP1, heptamer mimetic 16 (Kd =2.72â µm) displayed a higher affinity than decamer JIP1 (Kd =23.6â µm). The high affinity of 16 implies that the characteristic γ-turn mimetic structure, ""Φ-X-Φ" hydrophobic motif in 16, increased its affinity toward the JIP-site of JNK3.
Subject(s)
Ligands , Mitogen-Activated Protein Kinase 10/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Adaptor Proteins, Signal Transducing/chemical synthesis , Adaptor Proteins, Signal Transducing/chemistry , Adaptor Proteins, Signal Transducing/metabolism , Allosteric Regulation , Amino Acid Sequence , Binding Sites , Mitogen-Activated Protein Kinase 10/metabolism , Molecular Docking Simulation , Peptide Fragments/chemical synthesis , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Peptidomimetics , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Surface Plasmon ResonanceABSTRACT
A cell membrane permeable phosphopeptide corresponding to the SHP-2 binding motif of Grb2-associated binder 1 (Gab1) interferes with the Gab1 adaptor-dependent functions and modulates B cell receptor-triggered intracellular signaling in B cell tumors.
