The ubiquitin system is important for drug discovery, and the discovery of selective small-molecule inhibitors of deubiquitinating enzymes (DUBs) remains an active yet extremely challenging task. With a few exceptions, previously developed inhibitors have been found to bind the evolutionarily conserved catalytic centers of DUBs, resulting in poor selectivity. The small molecule IU1 was the first-ever specific inhibitor identified and exhibited surprisingly excellent selectivity for USP14 over other DUBs. However, the molecular mechanism for this selectivity was elusive. Herein, we report the high-resolution co-crystal structures of the catalytic domain of USP14 bound to IU1 and three IU1 derivatives. All the structures of these complexes indicate that IU1 and its analogs bind to a previously unknown steric binding site in USP14, thus blocking the access of the C-terminus of ubiquitin to the active site of USP14 and abrogating USP14 activity. Importantly, this steric site in USP14 is very unique, as suggested by structural alignments of USP14 with several known DUB X-ray structures. These results, in conjunction with biochemical characterization, indicate a coherent steric blockade mechanism for USP14 inhibition by compounds of the IU series. In light of the recent report of steric blockade of USP7 by FT671, this work suggests a potential generally applicable allosteric mechanism for the regulation of DUBs via steric blockade, as showcased by our discovery of IU1-248 which is 10-fold more potent than IU1.

Development of non-noble metal electrocatalysts for hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR) in acid is a great challenge for the development of polymer electrolyte membrane water electrolysis (PEMWE) and polymer electrolyte membrane fuel cells (PEMFC). Here, we report an efficient strategy for modulating the electron density of MoO2 by Ni doping to accelerate HER and HOR in acid. This is particularly important for PEMWE, PEMFC, and regenerative fuel cells. X-ray absorption spectroscopy demonstrates that Ni is doped by replacing Mo atoms in MoO2. Then Ni doping can lead to electron deficiency on neighboring O sites, which are induced to adsorb hydrogen and then increase the surface hydrogen coverage. Therefore, the doping of Ni can modulate the electron density of MoO2 for accelerating HER and HOR. Our results indicate that the incorporation of a high-electronegativity transition metal into MoO2 provides a new strategy for replacing Pt as an electrocatalyst for HER and HOR in acid.

Defect engineering is a well‐established approach to customize the functionalities of perovskite oxides. In demanding high‐power applications of piezoelectric materials, acceptor doping serves as the state‐of‐the‐art hardening approach, but inevitably deteriorates the electromechanical properties. Here, a new hardening effect associated with isolated oxygen vacancies for achieving well‐balanced performances is proposed. Guided by theoretical design, a well‐balanced performance of mechanical quality factor (Qm) and piezoelectric coefficient (d33) is achieved in lead‐free potassium sodium niobate ceramics, where Qm increases by over 60% while d33 remains almost unchanged. By atomic‐scale Z‐contrast imaging, hysteresis measurement, and quantitative piezoresponse force microscopy analysis, it is revealed that the improved Qm results from the inhibition of both extrinsic and intrinsic losses while the unchanged d33 is associated with the polarization contributions being retained. More encouragingly, the hardening effect shows exceptional stability with increasing vibration velocity, offering potential in material design for practical high‐power applications such as pharmaceutical extraction and ultrasonic osteotomes.

The development of alkaline polymer electrolyte fuel cells and alkaline water electrolysis requires nonprecious metal catalysts for the hydrogen oxidation reaction (HOR) and hydrogen evolution reaction (HER). Herein, it is reported a phase‐separated Mo–Ni alloy (PS‐MoNi) that is composed of Mo metal and embedded Ni metal nanoparticles. The PS‐MoNi shows excellent hydrogen electrode activity with a high exchange current density (−4.883 mA cm−2), which is comparable to the reported highest value for non‐noble catalysts. Moreover, the amorphous phase‐separated Mo–Ni alloy has better structural and electrochemical stability than the intermetallic compound Mo–Ni alloy (IC‐MoNi). The breakdown potential of PS‐MoNi is as high as 0.32 V, which is much higher than that of reported IC‐MoNi. The X‐ray absorption near edge structure (XANES) and density functional theory (DFT) calculations indicate the electrons transfer from Mo to Ni for PS‐MoNi, leading to suitable adsorption free energies of H* (ΔGH*) on the surface of Mo. This means that the electron density modulation of Mo metal by embedded Ni metal nanoparticles can produce excellent HOR and HER performance.

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