Section 23.4.4.2.5. Protein kinase A

The comparative study of water molecules in seven different protein kinase A structures in complex with different ligands focused exclusively on the active site (Shaltiel et al., 1998). All of the structures were solved from isomorphous crystals to resolutions ranging from 2.0 to 2.9 Å. The more lenient cutoff of 1.5 Å for the radius of the sphere within which the conserved water molecules must be found among the different structures is consistent with the relatively low resolutions of the structures included in this study. The group of structures represents the open, the closed and an intermediate conformation of the catalytic kinase domain. There is a set of six conserved water sites in the active site, in addition to the ATP molecule and the magnesium ion. The conserved water molecules coordinate to ATP, the metal ion and a conserved Tyr residue from the carboxyl terminus of the protein. Thus, the active site consists of an extended network of interactions that weave together both domains of the core, with water molecules playing an integral role in maintaining the structural features important for catalysis. Many of these water molecules associate directly with the inhibitors. In addition, five water sites are observed in positions that would be occupied by substrates or substrate analogues. These water molecules are displaced by ligand oxygen atoms that can compensate for the water hydrogen-bonding interaction with the protein.