Protein kinase inhibition: natural and synthetic variations on a theme.

How a protein kinase is turned off is as critical for its physiological function as is its catalytic activity. Examination of solved crystal structures representing different protein kinase subfamilies reveals a variety of strategies that are utilized by nature to lock protein kinases into inactive conformations. Pseudosubstrate and adenine mimetic mechanisms as well as complementarity to surfaces other than the active site are effective. Although most synthetic or natural product inhibitors target the active site, specifically the ATP binding site, a remarkably high degree of specificity can be achieved which is due to the extended surface of the protein that these inhibitors occupy. Although targeting of the ATP binding site is proving to be very successful, there is also wide latitude for designing inhibitors that target other surfaces of the kinases.