Conformational diversity of catalytic cores of protein kinases

Xray crystallography of the protein kinase family has provided an impressiv e array of crystal structures, setting the stage for rational design of spe cific inhibitors of these vitally important regulators of the signaling pat hways of the cell. Initial work on the first crystal structure of a protein kinase, cyclic AMP-dependent protein kinase, has provided evidence of conf ormational changes suggested to be critical for the common catalytic event of transferring the gamma phosphate from ATP onto the targeted protein. Thi s review updates the current status of the extent of conformational diversi ty of the protein kinase family and suggests that both the nature and the e xtent of those changes can provide a rationale for the increased occurrence of specific protein kinase inhibitors targeted at the ATP binding site. It focuses on the fact that in addition to the sequence diversities in ATP bi nding clefts reported recently, there is conformational diversity in the be ta sheets of the upper domains of the catalytic cores. This difference is d irectly related to the regulation of kinases by multiple mechanisms. (C) 19 99 Elsevier Science Inc. All rights reserved.