Kinase, kinases binding modes

Furet P, Caravattti G, Priestle J, Sowadski J, Trinks U, Traxler P. Modeling study of protein kinase inhibitors Binding mode of staurosporine-origin of the selectivity of CGP 52 411. J Comp Aid Mol Design 1995 9 465-472. 

Type I and type II kinase inhibitor binding modes are exemplified in Figure 3.3, which shows PD166326 (6, a) and imatinib (7, b) bound to ABL, represented by ribbon structures (PDB lOPK,11 and IIEP,12 respectively). In the latter, the DFG-out conformation of the activation loop reveals the allosteric site occupied by the benzylpiperazine moiety of imatinib, 7. 

Figure 3.3 Comparison of Type I (a) and Type II (b) kinase inhibitor binding modes.

It is difficult to deconvolute how kinase inhibitor binding mode has implications in the clinic. In general, selectivity tends to increase in the order (i) purine site, (ii) selectivity pocket, and (iii) allosteric site. The ability to overcome resistance mutations in cancer therapy tends to be inversely related to this selectivity pattern. Accordingly, allosteric kinase inhibition may become a preferred mechanism for clinical indications other than cancer. 

Figure 6.5 Overlay of the co-crystal structures of Abbott s alkynylpyrimidine 15 (brown) and the prototypical nucleoside inhibitor 5-IT (20, cyan) bound to adenosine kinase. The binding mode of 5-IT shows H-bonds from the ribose 2 -OH and 3 -OH to Asp-18. The exocyclic amine is engaged in a water-mediated H-bond to the main chain of Phe-170 and the side chain of Ser-173. One of the pyrimidine nitrogens interacts with the nitrogen of the side chain of Asn-14, while the other bonds to the main-chain nitrogen of Ser-65. The Abbott inhibitor (15) is engaged in the same interactions with Ser-65 and Asn-14. The morpholinopyridine intersects the space between the Phe-201 and Leu-40 side chains, causing a significant conformational change of the enzyme (compare brown and cyan ribbons).

The binding mode of the aminoquinazoline inhibitor, erlotinib, is consistent with that which had been observed previously for the intracellular kinases CDK2 and p38 [29]. The N1 and C8 edge of the heterocycle is oriented toward the hinge, with N1 accepting a hydrogen bond from Met769. N3... 

While no MEK apo structures have been published, comparisons to the catalytic domains of similar kinases reveal a number of differences versus the tertiary structure of MEKl. Relative to a crystal structure of PKA, there is an outward rotation of the N-terminal portion of hehx C by approximately 10 A and the formation of a short, two-turn a-hehcal segment of the activation loop. Both of these changes give rise to the allosteric binding pocket which enables the unique binding mode. Inhibitors such as PD318088 stabi-... 

Key words Protein kinase, kinase-targeted library, library design, kinase chemical cores, substructure search, SMARTS Query, subsetting, binding mode annotation. 

The overall design workflow for the KTL is schematically depicted in Fig. 14.4. In order to capture the majority of the known kinase chemotypes that represent the various binding modes, we first compiled a set of substructure queries based on... 

Kovari, Z. Flachner, B. Naray-Szabo, G. Vas, M. Crystallographic and thiol-reactivity studies on the complex of pig muscle phosphoglycerate kinase with ATP analogues correlation between nucleotide binding mode and helix flexibility. Biochemistry, 41, 8796-8806 (2002)... 

McEvoy, M.M. Hausrath, A.C. Randolph, G.B. Remington, S.J. Dahl-quist, F.W. Two binding modes reveal flexibility in kinase/response regulator interactions in the bacterial chemotaxis pathway. Proc. Natl. Acad. Sci. USA, 95, 7333-7338 (1998)... 

Three major clusters (1-3) are labeled on the left side of the heat map and also a cluster corresponding to the DFG-out conformation of the kinases, (b) Comparison of the binding modes of the three different kinase clusters. 

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