Related kinases pockets

Some proteins have not crystallized despite considerable effort. In such cases, mutation of a closely related kinase to resemble the kinase of interest has provided valuable structural information. Ikuta and co-workers mutated three residues within the ATP binding pocket of CDK2 to the corresponding residues in CDK4. The resulting mutant protein was crystallized and used to design CDK4-se-lective inhibitors [55]. 

Also related to Src kinase structural biology have been studies on two SFKs, namely Lck and Fyn. Importantly, the X-ray structure of Lck kinase was the first SFK determined [64] as complexes with AMP-PNP, staurosporine and PP2. Furthermore, a Fyn kinase-staurosporine complex has been recently described [65]. Extrapolating from the above Src kinase inhibitor crystal structures with respect to the hydrophobic specificity pocket and the active conformation of the protein to bind ATP-competitive inhibitors of varying templates and functional group elaboration, a working hypothesis of known Src kinase inhibitors (vide infra) can be suggested (Fig. 4). 

It is difficult to deconvolute how kinase inhibitor binding mode has implications in the clinic. In general, selectivity tends to increase in the order (i) purine site, (ii) selectivity pocket, and (iii) allosteric site. The ability to overcome resistance mutations in cancer therapy tends to be inversely related to this selectivity pattern. Accordingly, allosteric kinase inhibition may become a preferred mechanism for clinical indications other than cancer. 

The role of each cyclin is to achieve a specific CDK and direct the activated kinase complex to the appropriate substrate. The activated phosphorylated substrates then execute the key steps in cell-cycle progression. Active CDK/cyclin holoenzymes are presumed to hyperphosphorylate pRb and the related pocket proteins pi07 and pi30 from mid G1 to mitosis. The interaction among members of the E2F family of transcription... 

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