Principles governing the binding of a class of non-peptidic inhibitors to the SH2 domain of src studied by X-ray analysis.
Basic Information
ID: ALA1135493
Journal: J Med Chem
Title: Principles governing the binding of a class of non-peptidic inhibitors to the SH2 domain of src studied by X-ray analysis.
Authors: Lange G, Lesuisse D, Deprez P, Schoot B, Loenze P, Bénard D, Marquette JP, Broto P, Sarubbi E, Mandine E.
Abstract: A total of 11 structures of the (pp60)src SH2 domain with non-peptidic inhibitors based on the same two closely related inhibitor scaffolds were determined using X-ray crystallography. Surprisingly, the inhibitors that have an IC(50) value between 4 and 2700 nM bind in three different binding modes. Structure comparisons show that the inhibitors aim to maximize the interaction between the hydrophobic substituent and the hydrophobic pY+3 pocket. This is achieved either by an alternative binding mode of the phenyl phosphate or by including water molecules that mediate the interaction between the inhibitor scaffold and a rigid surface of the SH2 domain. The combination of the rigid pY+3 pocket and the rigid protein surface to which the scaffolds bind results in severe distance and angular restraints for putative scaffolds and their substituents. The X-ray data suggest that these restraints seem to be compensated in our system by including water molecules, thereby increasing the flexibility of the system.
CiteXplore: 12086479
DOI: 10.1021/jm0110800
Patent ID: ┄