Abstract
p38 mitogen-activated protein kinases are signaling molecules with major involvement in cancer. A detailed mechanistic understanding of how p38 MAPK family members function is urgently warranted for cancer targeted therapy. The conformational dynamics of the most common member of p38 MAPK family, p38α, are crucial for its function but poorly understood. Here we found that, unlike in other cancer types, p38α is significantly activated in pancreatic adenocarcinoma samples, suggesting its potential for anti-pancreatic cancer therapy. Using a state of the art supercomputer, Anton, long-timescale (39 μs) unbiased molecular dynamics simulations of p38α show that apo p38α has high structural flexibility in six regions, and reveal potential catalysis mechanism involving a “butterfly” motion. Moreover, in vitro studies show the low-selectivity of the current p38α inhibitors in both human and mouse pancreatic cancer cell lines, while computational solvent mapping identified 17 novel pockets for drug design. Taken together, our study reveals the conformational dynamics and potentially druggable pockets of p38α, which may potentiate p38α-targeting drug development and benefit pancreatic cancer patients.
Highlights
P38α Dynamics for Pancreatic Cancer a 135-residue N-terminal domain mainly composed of β-sheets and a 225-residue C-terminal domain mainly composed of αhelices, in between of which lies the catalytic site, i.e., the ATP-binding pocket [9, 10]
By screening pancreatic adenocarcinoma (PDAC) patient samples (n = 40) and The Cancer Genome Atlas (TCGA) database, we demonstrated that p38 MAPKs, especially p38α are highly expressed and activated. p38α blockades show significant antitumor effect in PDAC cells, but are not selective enough
We have found that the majority of the tumor tissues express similar level of p38 MAPKs to its adjacent healthy tissues, while uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC), and chromophobe renal cell carcinoma (KICH) show decreased p38α (MAPK14), p38β (MAPK11), and p38γ (MAPK12) expression compared with control pancreas
Summary
P38 mitogen-activated protein kinases (MAPKs) play critical roles in cellular responses, proliferation, survival, cell cycle, and migration in cancer. p38 MAPK family includes p38α (MAPK14), p38β (MAPK11), p38γ (MAPK12), and p38δ (MAPK13). NMR experiments of p38α in apo and ligand-bound forms suggested that the ATP-binding pocket is highly flexible even after ligand binding [16, 17] These studies reveal the important roles of conformational dynamics in the activation and catalysis of p38α. It is rational to speculate that next-generation highly selective p38 MAPK inhibitors may exhibit less adverse effects It still requires further investigation in cancer patients. Computational solvent mapping reveals 17 novel pockets that are potentially druggable for cancer therapy To our knowledge, this is the first comprehensive study of both the conformational dynamics and potentially druggable pockets in p38α. This study provides insights into understanding the molecular mechanism of p38α function and into developing potential drugs with high specificity and selectivity against PDAC
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