Abstract
p38α is a Ser/Thr protein kinase involved in a variety of cellular processes and pathological conditions, which makes it a promising pharmacological target. Although the activity of the enzyme is highly regulated, its molecular mechanism of activation remains largely unexplained, even after decades of research. By using state-of-the-art molecular dynamics simulations, we decipher the key elements of the complex molecular mechanism refined by evolution to allow for a fine tuning of p38α kinase activity. Our study describes for the first time the molecular effects of different regulators of the enzymatic activity, and provides an integrative picture of the activation mechanism that explains the seemingly contradictory X-ray and NMR data.
Highlights
We projected the free-energy surfaces (FESs) along two collective variables (CVs) - CV1 and CV2, both of which are based on the activation loop (A-loop) contacts that measure the distance from the crystallographically observed inactive (CV1) and active (CV2) conformations, and which were successfully used previously to study protein kinases (Sutto et al, 2012; Sutto and Gervasio, 2013; Marino et al, 2015)
In the clever paraphrase of Tolstoy’s Anna Karenina, Noble et al (Noble et al, 2004) stated how all active kinases are alike but an inactive kinase is inactive after its own fashion - referring to the attractiveness of the inactive form in the everlasting search for inhibitor selectivity
Based on the apo X-ray structure of p38a-pTpY (Zhang et al, 2011b), the phosphorylation event has been perceived as the trigger for the conformational change in which the A-loop moves away from the ATP-binding site enabling the N- and C-lobes to reorient and align the residues necessary for the ATP stabilization
Summary
P38 Ser/Thr kinases are mitogen-activated protein kinases (MAPKs) involved in the regulation of multiple cellular processes, including cell proliferation, differentiation, senescence, and death (Cuadrado and Nebreda, 2010). C-lobe segment, the L16 loop contains an acidic patch, called the common docking (CD) motif (Tanoue et al, 2000), which together with the hydrophobic groove, formed by the linker between aD and aE helices, and the b7-b8 reverse turn ( termed the ED site) (Chang et al., 2002) (Figure 1a), defines the peptide docking site recognized by the conserved docking motif present in activators, substrates, and regulators of MAPKs. The docking site enhances the specificity of MAPKs’ interactions, as well as its activity, albeit through an unknown molecular. We obtained a high level of sampling (>115 ms) which allowed us to explore the molecular mechanism of p38a canonical activation in unprecedented detail and reconcile the apparently contradictory X-ray and NMR data
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