Journal
JOURNAL OF PHYSICAL CHEMISTRY A
Volume 115, Issue 16, Pages 3895-3904Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jp108286r
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The regulation of protein kinases requires flexibility, especially near the ATP binding site. The cancer drug target Aurora A is inhibited by the ATP site inhibitor VX680, and published crystal structures show two distinct conformations. In one, a refolded glycine-rich loop creates a stacked pi-pi interaction between the conserved aromatic residue of the glycine-rich loop hairpin turn (F144) and the inhibitor. This refolding, associated with binding to a peptide derived from the cofactor TPX2, is absent in the other structure. We use surface plasmon resonance to measure VX680 binding to native and mutant F144A. Aurora A kinase domains, with and without the TPX2 peptide. Results show that the F144 aromatic side chain contributes 2 kcal/mol to the VX680 binding energy, independent of the TPX2 peptide. This indicates that distinct VX680 bound conformations of Aurora A cannot be simply correlated with TPX2 binding and that Aurora A retains flexibility when inhibitor-bound. Molecular dynamics simulations show that alternate geometries for the pi-pi interactions are feasible in the absence of the rigidifying packing interactions seen in the crystal lattice.
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