Kinases

Kinases are enzymes that catalyze the transfer of a phosphate group onto a substrate protein. Phosphorylation changes their activity, localization, stability, an/or interactions. Protein kinases form one of the largest enzyme families in eukaryotes and are central regulators of nearly all cellular processes. The enzymatic activity depends on the kinase, but often they recognize specific sequences of amino acids and modify one or more of Tyr, Thr, and Ser. Although different detailed mechanisms exist, in general kinases stabilize a high-energy intermediate such as through the presence of positively-charged residues nearby.

Processes like phosphorylation is a particularly important Post-Translational Modification (PTMs), so named because they allow proteins to be modified in real-time after alredy been translated (RNA->Protein). PTMs allow for a single protein sequence to have multiple distinct functional states. By decorating a protein’s surface exposed polar sidechain with a large, negatively charged group, the conformational ensemble the protein exists in can be signficantlly perturbed. Often, phosphorylation allows the protein to enter some kind of “active” state. There are often pairs of enzyme classes to reverse each other’s work; for example, the enzyme class which removes phosphate groups is called phosphatase.

Abl kinase bound to inhibitor Gleevec (1iep)

The structure below contains two identical copies of the Abl kinase bound to a very important chemotherapeutic drug, imatinib (sold as Gleevec). Gleevec transformed the prognosis of patients with chronic myeloid leukemia, and is still used today.

Because kinases are critical for cell signalling, mutations can readily cause abnormally high cellular signalling for growth or proliferation, which may lead to cancer. Abl is a very important tyrosine kinase involved in regulating cell growth and survival. Its kinase domain (below) adopts a canonical 2-lobe fold seen in protein kinases: a \(\beta\)-sheet rich lobe (N-terminal), an \(\alpha\)-sheet rich lobe (C-terminal), and the ATP binding site in the cleft between the two lobes. In this structure, the ground-breaking “miracle” drug, called imatinib and sold as Gleevec, is bound at that site. This drug was developed to bind selectively to this kinase, which becomes overactive after certain genetic mutations. Designing kinase inhibitor which are potent and selective for other kinases is a task which remains quite challenging due to the high sequence/structural similarity among various kinases.