Principles governing the binding of a class of non-peptidic inhibitors to the SH2 domain of src studied by X-ray analysis.
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.
Lange
Gudrun
G
Aventis Pharma, 102 Route de Noisy, 93235 Romainville, France.
Lesuisse
Dominique
D
Deprez
Pierre
P
Schoot
Bernard
B
Loenze
Petra
P
Bénard
Didier
D
Marquette
Jean-Pierre
JP
Broto
Pierre
P
Sarubbi
Edoardo
E
Mandine
Eliane
E
D001713:Biphenyl Compounds / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D008024:Ligands; D016392:Proto-Oncogene Proteins pp60(c-src)