1is0
From Proteopedia
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Crystal Structure of a Complex of the Src SH2 Domain with Conformationally Constrained Peptide Inhibitor
Overview
Isothermal titration calorimetry and X-ray crystallography have been used, to determine the structural and thermodynamic consequences associated with, constraining the pTyr residue of the pYEEI ligand for the Src Homology 2, domain of the Src kinase (Src SH2 domain). The conformationally, constrained peptide mimics that were used are cyclopropane-derived, isosteres whereby a cyclopropane ring substitutes to the N-Calpha-Cbeta, atoms of the phosphotyrosine. Comparison of the thermodynamic data for the, binding of the conformationally constrained peptide mimics relative to, their equivalent flexible analogues as well as a native tetrapeptide, revealed an entropic advantage of 5-9 cal mol(-1) K(-1) for the binding of, the conformationally constrained ligands. However, an unexpected drop in, enthalpy for the binding of the conformationally constrained ligands, relative to their flexible analogues was also observed. To evaluate, whether these differences reflected conformational variations in peptide, binding modes, we have determined the crystal structure of a complex of, the Src SH2 domain bound to one of the conformationally constrained, peptide mimics. Comparison of this new structure with that of the Src SH2, domain bound to a natural 11-mer peptide (Waksman et al. Cell 1993, 72, 779-790) revealed only very small differences. Hence, cyclopropane-derived, peptides are excellent mimics of the bound state of their flexible, analogues. However, a rigorous analysis of the structures and of the, surface areas at the binding interface, and subsequent computational, derivation of the energetic binding parameters, failed to predict the, observed differences between the binding thermodynamics of the rigidified, and flexible ligands, suggesting that the drop in enthalpy observed with, the conformationally constrained peptide mimic arises from sources other, than changes in buried surface areas, though the exact origin of the, differences remains unclear.
About this Structure
1IS0 is a Single protein structure of sequence from Rous sarcoma virus with PTC as ligand. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.
Reference
Calorimetric and structural studies of 1,2,3-trisubstituted cyclopropanes as conformationally constrained peptide inhibitors of Src SH2 domain binding., Davidson JP, Lubman O, Rose T, Waksman G, Martin SF, J Am Chem Soc. 2002 Jan 16;124(2):205-15. PMID:11782172
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