Phosphate binding region

Phosphate-binding region (PBR)- this hydrophilic region is highly solvent-exposed and seems unimportant for affecting affinity (see Section 7.2.1). 

An important observation by Naumann and Matter is the identification of additional opportunities to achieve selective interactions in the kinases phosphate binding region, whereas most work so far has focussed on the purine binding regions. 

Pai and coworkers also reported structural studies of several M. thermoau-totrophicum ODCase mutants (see Table 1) [19, 21]. These structural studies focused on how binding is affected when residues in the phosphate binding region, the recognition site for the 2- through 4-positions of the pyrimidine ring of bound inhibitors, and the Asp-Lys-Asp-Lys tetrad (see Fig. 4 and Table 2) are altered. 

Amino acid side chains at the positions X, Y, Z, -Y,-X, and —Z (illustrated in Fig. 29) of EF hands and other calcium-binding regions are listed. D, Aspartic acid E, glutamic acid N, asparagine S, serine T, threonine Ox, main-chain carbonyl Wa, water Ph, phosphate O -, a number of intervening amino acids. 

Fig. 2.8. Schematic representation of the interactions between the dimer contact surface of phosphofructokinase in the T- and R-state. The jagged lines mark part of the contact surface between an A and D subunit. The view is along the r axis, as in Fig. 2.7b, and thus along the contact surface between the AB and CD dimers, a) T-state In the T-state the two subunits interact tightly via salt bridges in the indicated region, b) R-state Fructose-6-phosphate binds in the cleft between the two subunits. The binding of ADP is also shown in the binding site for the ATP substrate. After Schirmer and Evans (1990), with permission.

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. 

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