Kinase adenine binding region

Adenine-binding region (ABR) - all ATP-competitive kinase inhibitors bind in this hydrophobic region and interact with the hinge domain via hydrogen bonds. 

Fig. 7. DOCK site point breakdown for the kinase receptor study. Three primary critical regions were defined (1) adenine acceptor zone, (2) adenine donor zone, (3) kinase ATP inhibitor rear hydrophobic pocket binding region. Adapted from ref. 70.

At present there are >100 protein kinase-inhibitor structures in publidy available structural databases which span 28 kinases and a variety of inhibitor structural classes. Based upon an analysis of these data a classification of ATP binding regions has been proposed by Traxler and Furet [59] and Bower (personal communication from Michael J. Bower, December 1999). In the subsequent discussion a slightly modified version of this classification will be used to organize the trends seen across kinases and inhibitor dasses (see Fig. 2.2). In the Traxler model, five sites were proposed of which three (adenine, sugar and phosphate-binding sites) can be directly related to ATP and two additional lipophilic sites which lay outside of the region occupied by ATP. In the Bower model, an additional polar site on the surface of the protein was proposed. 

The abundance of structural information has led to a significant increase in the use of structure-based methods both to identify and to optimise inhibitors of protein kinases. The focus to date has centred upon small molecule ATP-competitive inhibitors and there are numerous examples of protein-ligand complexes available to guide design strategies. ATP binds in the cleft formed between the N- and C-terminal lobes of the protein kinase, forming several key interactions conserved across the protein kinase family. The adenine moiety lies in a hydrophobic region between the jS-sheet structure of subdomains I and II and residues from subdomains V and VIb. A... 

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...

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