Mutant - inhibitor binding

Figure 6.3 Schematic illustration of the generation of inhibitor-insensitive kinase mutants. The interaction of ATP-site competitors with kinase domains has been structurally characterized through the so-called Traxler model [10]. The part of the inhibitor that corresponds to the adenine ring binds to the hinge region of the kinase domain via H bonds. Next to the hinge region are the hydrophobic back pocket and the surface-exposed front pocket, which do not play a role in ATP binding. However, these pockets are extremely critical determinants in inhibitor binding, since the...

Brier, S., Lemaire, D., DeBonis, S., Forest, E., and Kozielski, F. (2006) Molecular dissection of the inhibitor binding pocket of mitotic kinesin Eg5 reveals mutants that confer resistance to antimitotic agents. /. Mol. Biol. 360, 360-76. 

FEP has been successfully used to calculate stability of mutant pro-teins, to examine solvation properties,and to predict relative free energies of enzyme—inhibitor binding in the human immunodeficiency virus 1 (HIV-1) protease system,... 

Obviously, the inhibitor binds only weakly to the mutant enzyme and will diffuse out of the crystal lattice over time. This behavior can be explained when the interactions between this ligand and the mutant enzyme are analyzed in detail. Although the inhibitor occupies the exact same position as its counterpart in the native ODCase, there are only very few contacts left between nucleotide and protein matrix to hold the phosphate in place (Fig. 10). 

---