Allosteric regulation, the process by which a protein’s activity can be modulated by binding of an effector molecule distal to the active site, is vital for cellular signaling. However, its evolution is largely unexplored territory. I will describe our experimental exploration of the evolution over 1.5 billion years of two allosteric regulation mechanisms widely found in the modern protein kinase superfamily, phosphorylation of the activation loop and binding of a regulatory partner protein. Using Ancestral Sequence Reconstruction (ASR) we unravel the origins of allosteric activation including surprising mechanistic features. Moreover, ASR enabled identification of the underlying allosteric network that spans the kinase from the N-terminal to the C-terminal lobes. In the second part of the talk I describe how we exploit this new knowledge for the development of allosteric inhibitors and activators. This latter approach delivered novel kinase inhibitors and activators with extreme specificity and high affinity thereby opening the road to new cancer treatment.

Ancient origins of allosteric activation–Exploitation for novel cancer drugs

253rd National Meeting (2017)

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