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viruses. Specifically, it is the deregulation of the activity of protein kinases that leads to disease by
tumor viruses. The importance of this deregulation can be dramatically illustrated by the large number of
viral oncogenes (or cancer causing genes) that encode structurally modified protein kinases. These
deregulated enzymes are able to bypass the normal tightly regulated processes of growth control, leading
to acute malignant transformation. These oncogenes are one of the first examples of the identification of
disease-causing genes. Many of these viral genes have subsequently been implicated in human diseases.
Malignant tissues also share the common characteristic of an acquired independence from controls. The
receptor—for example, PDGF and EGFR—can be stimulated by a ligand coming either from the cell
itself (autocrine) or from nearby tissues (paracrine). Regardless of the mechanism leading to receptor
activity, the resulting kinase activity results in a cascade of signals that turn on cellular proliferation
programs. Therefore, selective inhibition of receptor tyrosine kinase will block tyrosine kinase driven
cell proliferation resulting in antitumor activity. In addition to cancer, a growing number of
nonmalignant proliferative diseases, (e.g., psoriasis, atherosclerosis, restenosis, fibrosis, etc.) or
inflammatory responses (e.g., septic shock, asthma, osteo and rheumatoid arthritis, etc.) involve
dysfunctional signaling pathways. Successful development of drugs that target this class of enzymes will
depend on the discovery of selective inhibitors designed for the appropriate protein kinase within the
family.
In the past several years there has been an explosion of structural studies within the protein kinase
family [1–8]. These studies, initiated by the crystal structure of Protein Kinase A [9–12] (CAPK) have
shown that all members of the protein kinase family fold into a uniform three-dimensional catalytic core.
Yet this uniform three-dimensional fold exhibits both different surface charges and at least two major
conformations.
II. Protein Kinase Template
The stereo view of the ribbon diagram of cAPK is presented in Figure 1a. The overall topology of the
core extending from strand 1 through helix h, Figure 1b, is identical (except helix B) with the eight other
structures of protein kinases determined to this point. Furthermore, Figure 2 presents an overall
structural comparison of the catalytic cores of the five kinases, cAPK, CDK2, CDK2-CYCLIN, IR, and
MAP. The N-terminal helix A, which is present only in the cAPK crystal structure, is anchored by
myristic acid in the mammalian bovine heart of cAPK. Myristic acid inserts itself into the hydrophobic
pocket of the lower lobe of the enzyme, which results in the structural ordering of helixA and Ser10[13],
one of the four autophosphorylation sites.
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