Gatekeeper residues

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). 

Table 7.4 Correlation between activity of SB203580 on a kinase and identity of its gatekeeper residue.

Fig. 2.2 (A) Traxler/Bower Kinase inhibitor pharmacophore. The perspective given is a top down view from the N-terminal to C-ter-minal domain in which the plane of the adenine ring matches that of the page. A short segment of the kinase linker region is shown which includes the three hydrogen bonding residues (minus side chains) plus the gatekeeper residue. In this orientation the top of...

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].

Figure 4 Protein kinases with the "gatekeeper" residue mutated to glycine that makes them recognize N -substituted ATP analogs also programs them to be uniquely sensitive to designed inhibitors, allowing rapid generation of potent selective kinase inhibitors of any protein kinase.

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... 

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