Send to

Choose Destination
Chem Biol. 2010 Nov 24;17(11):1241-9. doi: 10.1016/j.chembiol.2010.09.010.

Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.

Author information

Ambit Biosciences, 4215 Sorrento Valley Boulevard, San Diego, CA 92121, USA.


Interactions between kinases and small molecule inhibitors can be activation state dependent. A detailed understanding of inhibitor binding therefore requires characterizing interactions across multiple activation states. We have systematically explored the effects of ABL1 activation loop phosphorylation and PDGFR family autoinhibitory juxtamembrane domain docking on inhibitor binding affinity. For a diverse compound set, the affinity patterns correctly classify inhibitors as having type I or type II binding modes, and we show that juxtamembrane domain docking can have dramatic negative effects on inhibitor affinity. The results have allowed us to associate ligand-induced conformational changes observed in cocrystal structures with specific energetic costs. The approach we describe enables investigation of the complex relationship between kinase activation state and compound binding affinity and should facilitate strategic inhibitor design.

[Indexed for MEDLINE]
Free full text

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases


Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center