Overlayed kinase crystal structures

Figure 2.16 Subset of overlayed kinase crystal structures.

The inhibitor has been described as exquisitely selective across a panel of over 200 kinases due to the specific nature of the interactions it makes with the inactive form of cMET. ARQ 197 has been extensively characterised as non-ATP competitive by biochemical, biophysical and structural studies. X-Ray crystal structure studies of ARQ 197 bound to cMET (PDB 3RHK) provides specific rationale for the selectivity profile of the compound, where the protein is seen in a conformation which has not been observed for other protein kinases. Figure 2.10 shows the overlay with ARQ 197 bound in cMET (brown) with a structure of cMET bound with ATP (3DKC,20 cyan). For ease of viewing only key side chains have been included and ATP has been removed. 

Figure 6.3 Overlay of the co-crystal structures of 10 (cyan) and 12 (brown) with deoxycytidine kinase.35 The following interactions are indicated. Compound 10 H-bonds from the 5 -OH to Glu-53, Arg-128 and water from the 4 -OH to Glu-197 and Tyr-86 from the carbonyl to water to Tyr-204 and Tyr-86 from the pyrimidine N to the Gln-97 backbone carbonyl from the exocyclic NH2 to the Gln-97 backbone NH and the Asp-133 side chain and from F to Arg-104. The binding mode of compound 12 is characterized by a H-bond between the amide carbonyl and a conserved water molecule and by a water-mediated H-bond between the pyrimidine N and Tyr-86. The overlay of the two structures also clearly shows how a new pocket is created to accommodate the biaryl portion of compound 12 (cf. movement of Tyr-86).

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).

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