3RI1

Crystal structure of the catalytic domain of FGFR2 kinase in complex with ARQ 069

Summary for 3RI1

• Entry DOI: 10.2210/pdb3ri1/pdb
• Descriptor: Fibroblast growth factor receptor 2, (6S)-6-phenyl-5,6-dihydrobenzo[h]quinazolin-2-amine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: fgfr1 kinase, fgfr2 kinase, inactive conformation, kinase-inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 14: Secreted. Isoform 19: Secreted: P21802
• Total number of polymer chains: 2
• Total formula weight: 72941.64

Authors

Eathiraj, S.,Palma, R.,Hirschi, M.,Volckova, E.,Nakuci, E.,Castro, J.,Chen, C.R.,Chan, T.C.,France, D.S.,Ashwell, M.A. (deposition date: 2011-04-12, release date: 2011-05-04, Last modification date: 2024-10-30)

Primary citation

Eathiraj, S.,Palma, R.,Hirschi, M.,Volckova, E.,Nakuci, E.,Castro, J.,Chen, C.R.,Chan, T.C.,France, D.S.,Ashwell, M.A.
A novel mode of protein kinase inhibition exploiting hydrophobic motifs of autoinhibited kinases: discovery of ATP-independent inhibitors of fibroblast growth factor receptor.
J.Biol.Chem., 286:20677-20687, 2011

PubMed Abstract: Protein kinase inhibitors with enhanced selectivity can be designed by optimizing binding interactions with less conserved inactive conformations because such inhibitors will be less likely to compete with ATP for binding and therefore may be less impacted by high intracellular concentrations of ATP. Analysis of the ATP-binding cleft in a number of inactive protein kinases, particularly in the autoinhibited conformation, led to the identification of a previously undisclosed non-polar region in this cleft. This ATP-incompatible hydrophobic region is distinct from the previously characterized hydrophobic allosteric back pocket, as well as the main pocket. Generalized hypothetical models of inactive kinases were constructed and, for the work described here, we selected the fibroblast growth factor receptor (FGFR) tyrosine kinase family as a case study. Initial optimization of a FGFR2 inhibitor identified from a library of commercial compounds was guided using structural information from the model. We describe the inhibitory characteristics of this compound in biophysical, biochemical, and cell-based assays, and have characterized the binding mode using x-ray crystallographic studies. The results demonstrate, as expected, that these inhibitors prevent activation of the autoinhibited conformation, retain full inhibitory potency in the presence of physiological concentrations of ATP, and have favorable inhibitory activity in cancer cells. Given the widespread regulation of kinases by autoinhibitory mechanisms, the approach described herein provides a new paradigm for the discovery of inhibitors by targeting inactive conformations of protein kinases.

PubMed: 21454610
DOI: 10.1074/jbc.M110.213736

Experimental method

X-RAY DIFFRACTION (2.1 Å)