Structure-function and structure-inhibition relationships in the CDK family


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Martin Noble

University of Oxford, UK

Abstract

Structure-function and structure-inhibition relationships in the CDK family

Human protein kinases frequently exist in gene families that provide a remarkable robustness to signalling networks by virtue of their ability to functionally complement each other when the activity of one family member is selectively knocked down by chemical or genetic intervention. This presents a particular challenge to target selection and inhibitor design where low molecular weight chemical entities are the chosen route to interfering with kinase activity for therapeutic purposes. A comprehensive understanding of the structures available to different family members might contribute to an ability to target an appropriate subset of a particular gene family, and hence help to address this challenge. Similarly, a clear picture of how selectivity is dependent on the “inner shell” of amino acids that surround the inhibitor binding site, as compared to the outer shells of amino acids that provide long range conformational and electrostatic effects, can contribute to both target selection and inhibitor design. I will describe recent work looking at structures of the CDK family, with a view to understanding the structural variability within this important gene family. I will also describe the results of a mutagenesis strategy that has stepwise converted the inner shell of amino acids of CDK2 to the active site composition of CDK7, assessing at each step the extent to which an inhibitor’s eye view of the active site has changed accordingly.