Kinase, kinases orthogonal

Active Inhibitor-insensitive Kinase Mutants (Orthogonal Protein Kinases)... 

Coupled folding and binding is a frequent theme in the field of intrinsically disordered proteins (see Chap. 6). One of the earliest examples of this phenomenon was the interaction of the phosphorylated kinase-inducible domain (pKID) of the transcription factor CREB with the KIX domain of the transcriptional coactivator CBP. Free pKID is unfolded in solution [21], but folds into an orthogonal pair of helices, aA and aB, upon binding to the folded KIX domain (Fig. 1.5) [23]. We have recently posed the question, what is the... 

Both of these strategies have broader applications than the kinase signaling pathways. Orthogonal ligand-receptor pairs could, theoretically, be made for any ligand-receptor pair. These pairs could then be used to study metabolic pathways and protein function, to identify smaD-molecule ligands and other applications. 

Fig. 8.15 (A) X-ray crystal structure of PPl bound to Hck. Threonine-338 is analogous to phenyl-alanine-88 in cyclin-dependent kinase Cdc28. T88 was changed into a glycine in an attempt to create an orthogonal ligand-receptor pair. (B) Ligplot representation of PPl interaction with T338 [13]. Coordinates from lQCF[38j.

Fig. 8.16 The PP1 analogue that is an orthogonal ligand inhibitor specific for the F88G variant of the cyclin-dependent kinase Cdc28.

A large number of examples for the orthogonal dipolar C-F—C=0 interactions have been found in the CSD and PDB [101], For example, Figure 1.13b illustrates a rather unique double interaction, that is, C-F—(C=0)2, in the inhibitor-enzyme complex of 26 with p38 MAP kinase, wherein the fluorine atom of the 4-fluorophenyl moiety of 26 interacts with the amide carbonyl carbons of Leul04 and Vall05 with equal distance of 3.1 A [102],... 

Given the convergence between the resistance mutations found in cancer and the mutations used to engineer orthogonal kinase ligands, it is reasonable... 

S.M. Ulrich, O. Buzko, K. Shah, K.M. Shokat, Towards the engineering of an orthogonal protein kinase/ nucleotide triphosphate pair, Tetrahedron 2000, 56, 9495-9502. 

Figure 1.24 Orthogonal chemical genetics development of analog-sensitive kinase alleles (ASKAs).

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