Proteus in the World of Proteins: Conformational Changes in Protein Kinases

Abstract

The 512 protein kinases encoded by the human genome are a prime example of nature's ability to create diversity by introducing variations to a highly conserved theme. The activity of each kinase domain is controlled by layers of regulatory mechanisms involving different combinations of post-translational modifications, intramolecular contacts, and intermolecular interactions. Ultimately, they all achieve their effect by favoring particular conformations that promote or prevent the kinase domain from catalyzing protein phosphorylation. The central role of kinases in various diseases has encouraged extensive investigations of their biological function and three-dimensional structures, yielding a more detailed understanding of the mechanisms that regulate protein kinase activity by conformational changes. In the present review, we discuss these regulatory mechanisms and show how conformational changes can be exploited for the design of specific inhibitors that lock protein kinases in inactive conformations. In addition, we highlight recent developments to monitor ligand-induced structural changes in protein kinases and for screening and identifying inhibitors that stabilize enzymatically incompetent kinase conformations.

Computational Methods in Drug Discovery

“…Docking studies with kinases, however, indicate that similarity of binding site influences docking prediction (Tuccinardi et al, 2010). In addition, kinases' binding sites have high plasticity, allowing adaptation to interact with ligands (Rabiller et al, 2010). This makes for a good argument to go for ligand-induced homology modeling.…”

Structural basis for basal activity and autoactivation of abscisic acid (ABA) signaling SnRK2 kinases

“…S7). conformations that are adopted by active kinases (29,31,32). Many kinases, including AMPK, require activation loop phosphorylation for the conformational switch from inactive to active conformation.…”

“…2 B and C) and showed other hallmarks of active or partially active kinases (see below). Crystal structures of kinase domains typically provide snapshots within the ensemble of the different conformations that may be adopted in physiological settings (32). Because both SnRK2.3 and -2.6 share a similar level of basal activity, it is reasonable to assume that both kinases can adopt partially active conformations in their nonphosphorylated state.…”

Molecular Mechanism of Selectivity among G Protein-Coupled Receptor Kinase 2 Inhibitors

“…Because of the high conservation of the ATP-binding site among of the ϳ500 kinases, the majority of small molecule kinase inhibitors target the ATP-binding site in a binding mode similar to that of ATP itself, generally resulting in inhibitors that lack selectivity (Bogoyevitch and Fairlie, 2007). However, with the discovery of imatinib it became clear that the inactive conformation of a given kinase can be quite unique and therefore targeted to produce selective inhibitors (Noble et al, 2004;Breitenlechner et al, 2005a;Rabiller et al, 2010).…”