Rational design of inhibitors that bind to inactive kinase conformations

By Yi Liu, Nathanael S. Gray. Nature Chemical Biology, 2006

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How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

Comprehensive analysis of kinase inhibitor selectivity (2011, background): “We show that most type II inhibitors, which contact a binding pocket adjacent to the ATP site and prefer a 'DFG-out', inactive kinase conformatio”
Paul Ehrlich's magic bullet concept: 100 years of progress (2008, background): “Whereas type I inhibitors block the ATP binding site within the bi-lobe structure of the kinase domain, type II inhibitors bind and preferentially stabilize the inactive conformatio”
Targeting cancer with small molecule kinase inhibitors (2009, positive): “Most kinase inhibitors discovered to date are ATP competitive and present one to three hydrogen bonds to the amino acids located in the hinge region of the target kinase, thereby mimicking the hydrogen bonds that are normally formed by the adenine ring of AT”
Kinase-targeted cancer therapies: progress, challenges and future directions (2018, background): “The Phe in the DFG motif packs under the helix-C positioning both helix-C and A-loop for catalysis [98, 133, 136].”
Developing irreversible inhibitors of the protein kinase cysteinome (2013, neutral): “…the ATP-binding site with the kinase assuming an active conformation, or a conformation otherwise conducive to ATP binding, are called ‘‘type I’’ inhibitors while those that induce a ‘‘flip’’ of the DFG motif that marks the start of the activation loop are called ‘‘type II’’ (Liu and Gray, 2006).”