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Structure

Protein kinases (PKs) are enzymes that transfer phosphoryl group from an ATP molecule to Ser, Thr or Tyr residue of the substrate protein. The human genome consists 484 PK genes (497 domains) that are divided broadly into nine families based on their sequences namely, AGC, CAMK, CK1, CMGC, NEK, RGC, STE, TKL, TYR and OTHER (unclassified). They share a conserved structural fold consisting of two lobes: an N-terminal lobe, formed by five stranded β-sheet with an α-helix called the C-helix, and a C-terminal lobe comprising six α-helices. The two lobes are connected by a flexible region in the middle which forms the ATP binding active site of the protein.

Activation loop

The activation loop is typically 20-30 residues in length and is the most critical secondary structural element of the active site of PKs. It is in completely extended conformation in the catalytically active state of the enzyme facilitating the binding of ATP molecule and the substrate. However, it folds on the surface of the protein in different kinds of inactive states. The activation loop begins with a conserved sequence motif called DFGmotif (Asp, Phe, and Gly residues). These residues are observed to be in a unique orientation when the loop is extended (active state) but display remarkable flexibility in folded (inactive) loop conformations.