Dual-Action Kinase Inhibitors Influence p38α MAP Kinase Dephosphorylation.

Reversible protein phosphorylation directs essential cellular processes including cell division, cell growth, cell death, inflammation, and differentiation. Because protein phosphorylation drives diverse diseases, kinases and phosphatases have been targets for drug discovery, with some achieving remarkable clinical success. Most protein kinases are activated by phosphorylation of their activation loops, which shifts the conformational equilibrium of the kinase towards the active state. To turn off the kinase, protein phosphatases dephosphorylate these sites, but how the conformation of the dynamic activation loop contributes to dephosphorylation was not known. To answer this, we modulated the activation loop conformational equilibrium of human p38α ΜΑP kinase with existing kinase inhibitors that bind and stabilize specific inactive activation loop conformations. From this, we discovered three inhibitors that increase the rate of dephosphorylation of the activation loop phospho-threonine by the PPM serine/threonine phosphatase WIP1. Hence, these compounds are "dual-action" inhibitors that simultaneously block the active site and stimulate p38α dephosphorylation. Our X-ray crystal structures of phosphorylated p38α bound to the dual-action inhibitors reveal a shared flipped conformation of the activation loop with a fully accessible phospho-threonine. In contrast, our X-ray crystal structure of phosphorylated apo human p38α reveals a different activation loop conformation with an inaccessible phospho-threonine, thereby explaining the increased rate of dephosphorylation upon inhibitor binding. These findings reveal a conformational preference of phosphatases for their targets and suggest a new approach to achieving improved potency and specificity for therapeutic kinase inhibitors.

High-Selectivity Planar Thermal Emitter with a Stable Temperature over 1400 K for a Thermophotovoltaic System.

A selective thermal emitter with superior thermal stability and perfect selective thermal emission in specific bands can facilitate the lifting of the thermophotovoltaic (TPV) energy conversion efficiency in TPV systems. Scalable planar selective thermal emitters with superior spectral selectivity and robust high-temperature stability are desired to meet the requirements of large-scale deployments of TPV systems. However, stably reradiating the available thermal photons at above 1273 K remains a significant challenge for selective thermal emitters. In this work, we demonstrated a high-selectivity planar thermal emitter based on the composite ceramic of ZrC and Al2O3. The prepared selective thermal emitter provides an emissivity of around 90% above the photon energy (0.6 eV) at 1423 K, a strong emission suppression effect below 0.6 eV, and superior thermal stability up to at least 1423 K. Therefore, the overall spectral efficiency can reach around 53%. Coupled with an InGaAs PV cell, the TPV system based on the selective thermal emitter demonstrates a predicted heat-to-electricity power conversion efficiency of 29.78% at 1423 K due to the matched spectral response of the emitter with the PV cell. Our work opens a new way forward for TPV systems based on planar selective thermal emitters.