Allosteric regulation and inhibition of protein kinases

Abstract

The human genome encodes more than 500 different protein kinases: signaling enzymes with tightly regulated activity. Enzymatic activity within the conserved kinase domain is influenced by numerous regulatory inputs including the binding of regulatory domains, substrates, and the effect of post-translational modifications such as autophosphorylation. Integration of these diverse inputs occurs via allosteric sites that relate signals via networks of amino acid residues to the active site and ensures controlled phosphorylation of kinase substrates. Here, we review mechanisms of allosteric regulation of protein kinases and recent advances in the field.

Breaking the conformational ensemble barrier: Ensemble structure modeling challenges in CASP15

“…Kinases have been extensively characterized in terms of local structural and functional motifs, 21 providing a useful basis for evaluation. Figure 3 shows the motif regions for CASP targets.…”

The logic of protein post‐translational modifications (PTMs): Chemistry, mechanisms and evolution of protein regulation through covalent attachments

“…[22] The role of protein phosphorylation in the regulation of sugar metabolism by hormones and its extension to other signalling pathways and the cell cycle provide a powerful paradigm for thinking about PTMs as a regulatory switch. A related but somewhat separate field of research evolved around the structure, [23] allosteric regulation and small-molecule inhibition of canonical protein kinases, [24] which arguably remain the best-studied protein-modifying enzymes.…”

CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets

“…20 The catalytic activity of the kinase is a result of the integration of various inputs at the allosteric sites, such as the binding of regulatory domains and substrates, and the effect of posttranslational modifications, such as autophosphorylation. 21 The crystal structures of the cyclin-E/CDK2 complex show the active conformation with cyclin-E contacting both the Nand C-lobe of CDK2 (Figure 1), 22 whereas early structures of cyclin-D/CDK4 showed the inactive conformation with cyclin-D contacting only the N-lobe of CDK4, 23 leading to the expectation that CDK4 may require additional factors to reach the active state. Recently, the crystal structure of the active conformation of cyclin-D3/CDK4, in which cyclin-D3 contacts both the N-and C-lobes of CDK4, was resolved, showing significant differences from the early inactive conformations of cyclin-D/CDK4.…”

“…Kinases exist in equilibrium between active and inactive conformations, and extrinsic binding of regulatory molecules or proteins can allosterically shift this equilibrium, enhancing, or dampening their activity. , Among these, are p21 and p27 intrinsically disordered proteins that can inhibit or activate CDK2 and CDK4 depending on their phosphorylation state . The catalytic activity of the kinase is a result of the integration of various inputs at the allosteric sites, such as the binding of regulatory domains and substrates, and the effect of post-translational modifications, such as autophosphorylation …”

“… 20 The catalytic activity of the kinase is a result of the integration of various inputs at the allosteric sites, such as the binding of regulatory domains and substrates, and the effect of post-translational modifications, such as autophosphorylation. 21 …”