PROTEIN-KINASE INHIBITION - NATURAL AND SYNTHETIC VARIATIONS ON A THEME

How a protein kinase is turned off is as critical for its physiologica l 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 ki nases into inactive conformations. Pseudosubstrate and adenine mimetic mechanisms as well as complementarity to surfaces other than the acti ve site are effective. Although most synthetic or natural product inhi bitors target the active site, specifically the ATP binding site, a re markably high degree of specificity can be achieved which is due to th e extended surface of the protein that these inhibitors occupy. Althou gh targeting of the ATP binding site is proving to be very successful, there is also wide latitude for designing inhibitors that target othe r surfaces of the kinases. (C) Current Biology Ltd ISSN 1367-5931.