Allosteric communication is mediated by structural and dynamic changes that can be challenging to measure experimentally. To dissect these effects, we use a diverse array of spectroscopic techniques coupled with structure determination. These techniques are used to uncover new allosteric mechanisms and as tools to drive new inhibitor discovery.
Allostery in protein kinases
The protein kinases are signaling proteins of immense importance to human health, as they are key mediators of cell growth and division. Kinases have intricate regulatory mechanisms that ensure they are only catalytically active when appropriate, but oncogenic kinases typically have mutations that bypass this control, leading to constitutive kinase activity and cancer.
At first glance, kinases appear to have each evolved their own regulatory mechanisms, as the kinase domain is controlled by a diverse set of regulatory domains and subunits in different family members. Nevertheless, the precise conformational changes that the kinase domain undergoes in response to these diverse cues are in fact strikingly conserved. This suggests that all kinase domains have intrinsic allosteric potential that was moulded through evolutionary divergence into a bewildering array of different forms. We are pinpointing where the conservation of allostery gives way to divergence. This question has important practical implications for the selectivity of future allosteric kinase inhibitors, which hold great promise as the cancer drugs of tomorrow.
Double electron-electron resonance
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