Nat. Chem. Biol. 2021

CdK2 paper Abstract.tiff

We used a combination of double electron-electron resonance (DEER) spectroscopy, paramagnetic relaxation enhancement NMR, and fluorescence to study allosteric activation of cyclin-dependent kinase 2 in solution. We showed that phosphorylation of Cdk2 on the activation loop enhances allosteric coupling between the cyclin subunit and the kinase, and demonstrate that this allosteric coupling underlies the selective recognition of CDK inhibitors.

PNAS 2018

CdK2 paper Abstract.tiff

We used a new time-resolved FRET based method to profile the conformational effects of a large panel of Aurora kinase inhibitors on Aurora A. The results show clearly for the first time that the preference of inhibitors for the DFG-in or DFG-out states is the dominant determinant of selectivity, and that different DFG-out inhibitors differ by two orders of magnitude in their preference for the DFG-out state.

Biochem. J. 2018

CdK2 paper Abstract.tiff

The protein kinase Aurora A (AurA) is essential for the formation of bipolar mitotic spindles in all eukaryotic organisms. During spindle assembly, AurA is activated through two different pathways operating at centrosomes and on spindle microtubules. Recent studies have revealed that these pathways activate AurA through multifaceted changes to the structure and dynamics of the kinase domain.

eLife 2018

CdK2 paper Abstract.tiff

We used a diverse range of spectroscopic methods combined with long timescale molecular dynamics simulations to show that phosphorylation of the activation loop does not trap Aurora kinase A in the active DFG-in state as previously thought, and that the loop instead continues to transition between the DFG-in and DFG-out states.

Nat. Chem. Biol. 2017

CdK2 paper Abstract.tiff

We used an infrared probe to show that allosteric activation of the mitotic kinase Aurora A by the spindle-associated protein Tpx2 is a two-step process, involving both a conformatonal shift towards the active DFG-In state, and an enhancement of the intrinsic activity of the DFG-In state through tuning of a novel allosteric network mediated by structured water molecules.

Nat. Chem. Biol. 2014

CdK2 paper Abstract.tiff

Type I kinase inhibitors exploit structured water molecules in the ATP-binding site to recognize their kinase targets. These interactions turn out to be energetically significant and make a big contribution to the selectivity that inhibitors display for different kinases.

PLoS ONE 2012

CdK2 paper Abstract.tiff

Bosutinib is a second-generation Abl kinase inhibitor used in the treatment of chronic myeloid leukemia. We determined the first crystal structure of this drug bound to the Abl kinase domain. The structure explains the effects of several resistance mutations that arise in patients during tyrosine kinase inhibitor therapy.

Cell 2008

CdK2 paper Abstract.tiff

Src kinase, the prototypical oncogene, is catalytically inactivated through phosphorylation on a C-terminal tyrosine residue. The kinase responsible, Csk, only phosphorylates the Src kinases. We illuminated the structural basis for this unusual specificity by cocrystallizing the two proteins.

PLoS Biology 2006

CdK2 paper Abstract.tiff

The distantly related tyrosine kinases Src and Abl were previously thought to have unrelated allosteric activation mechanisms. Here we showed that Abl can in fact adopt an inactive conformation that looks almost identical to the canonical inactive conformation of Src, demonstrating that the conformational states that protein kinases adopt are broadly conserved across this protein family.

Selected publications on kinase structure and dynamics