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The ATP site of kinases displays remarkable conformational flexibility when accommodating chemically diverse small molecule inhibitors. The so-called activation segment, whose conformation controls catalytic activity and access to the substrate binding pocket, can undergo a large conformational change with the active state assuming a 'DFG-in' and an inactive state assuming a 'DFG-out' conformation. Compounds that preferentially bind to the DFG-out conformation are typically called 'type II' inhibitors in contrast to 'type I' inhibitors that bind to the DFG-in conformation. This review surveys the large number of type II inhibitors that have been developed and provides an analysis of their crystallographically determined binding modes. Using a small library of type II inhibitors, we demonstrate that more than 200 kinases can be targeted, suggesting that type II inhibitors may not be intrinsically more selective than type I inhibitors.

Original publication

DOI

10.1021/cb500129t

Type

Journal article

Journal

ACS Chem Biol

Publication Date

20/06/2014

Volume

9

Pages

1230 - 1241

Keywords

Animals, Drug Discovery, Humans, Protein Binding, Protein Conformation, Protein Kinase Inhibitors, Protein Kinases