Gatekeeper pocket

The pyridinyl amide makes two hydrogen-bonding contacts to the main chain of Cys531, while the central aryl ring occupies the gatekeeper pocket—... 

Binding region I (BR-I) - this pocket extends in the direction of the N6 of ATP and is not involved in binding ATP. This region is not conserved and is used to improve affinity as well as selectivity. Access to this region is controlled by the so-called gatekeeper residue (see Section 7.4.2.2). 

Tab. 2.2 The effect of site-specific mutagenesis of gatekeeper residues Met-106 p38y) and Thr-338 (Src) on inhibitors which occupy the gatekeeper specificity pocket [74, 75].

Some compounds extend from a purine site into an adjacent hydrophobic region, which is not thought to be used by natural ligands and is often known as the selectivity pocket (Figure 4.3). This is an allosteric site, because it is not used by substrates of the enzyme. The selectivity pocket is so named because it is not well conserved and inhibitor selectivity often correlates with the identity of a gatekeeper residue at the entrance to the pocket, occurring 3 residues before the main-chain NH donor in the purine site. Most compounds that use... 

In addition to a direct effect on the shape and character of the binding pocket, recent mutagenesis suggests that gatekeeper mutations in several... 

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