The dynamic nature of transglutaminases

Transglutaminases incorporate a variety of primary amines into specific glutamine residues of target proteins in a transamidation reaction: the incorporation of lysine residues result in protein crosslinks, while the incorporation of small amines result in protein-amine conjugates. Transglutaminases play important but poorly understood roles in many diseases, and greater knowledge of their catalytic activity will provide valuable insight. This study provides evidence for a new transglutaminase mechanism-of-action: dynamic protein crosslinking via continuous interchange between incorporated lysines and incorporated amines. This finding contributes to a greater understanding of transglutaminase biology and potentially opens new avenues for disrupting disease processes

Membrane-protein crystals for neutron diffraction

Neutron macromolecular crystallography (NMX) has the potential to provide the experimental input to address unresolved aspects of transport mechanisms and protonation in membrane proteins. However, despite this clear scientific motivation, the practical challenges of obtaining crystals that are large enough to make NMX feasible have so far been prohibitive. Here, the potential impact on feasibility of a more powerful neutron source is reviewed and a strategy for obtaining larger crystals is formulated, exemplified by the calcium-transporting ATPase SERCA1. The challenges encountered at the various steps in the process from crystal nucleation and growth to crystal mounting are explored, and it is demonstrated that NMX-compatible membrane-protein crystals can indeed be obtained

Photoswitchable Inhibitors of the Sarco(endo)plasmic Calcium Pump

Targeting the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) offers a promising strategy for treating drug-resistant cancers. However, as SERCA activity is essential for all cells types, specific inhibitors such as thapsigargin (TG) possess general toxicity. We explored the potential for developing SERCA inhibitors controllable with light by synthesizing TG derivatives containing an azobenzene photoswitch. These compounds (AzTG derivatives) were assessed by their ability to inhibit SERCA ATPase activity. We have identified cis-active and trans-active derivatives and our results reveal a ~2-fold difference in IC50 in response to photoisomerization, demonstrating an effect of the incorporated photoswitch. Furthermore, X-ray structures of SERCA in complex with two AzTG derivatives were obtained, revealing two different binding modes for the photoswitch group of these compounds. Taken together, we have developed photo-activatable SERCA inhibitors that can serve as tools to study the function of their target protein, and our results build the foundation for the design of improved, next-generation photoswitchable inhibitors

Quantum Information Science and Technology for Nuclear Physics. Input into U.S. Long-Range Planning, 2023

In preparation for the 2023 NSAC Long Range Plan (LRP), members of the Nuclear Science community gathered to discuss the current state of, and plans for further leveraging opportunities in, QIST in NP research at the Quantum Information Science for U.S. Nuclear Physics Long Range Planning workshop, held in Santa Fe, New Mexico on January 31 - February 1, 2023. The workshop included 45 in-person participants and 53 remote attendees. The outcome of the workshop identified strategic plans and requirements for the next 5-10 years to advance quantum sensing and quantum simulations within NP, and to develop a diverse quantum-ready workforce. The plans include resolutions endorsed by the participants to address the compelling scientific opportunities at the intersections of NP and QIST. These endorsements are aligned with similar affirmations by the LRP Computational Nuclear Physics and AI/ML Workshop, the Nuclear Structure, Reactions, and Astrophysics LRP Town Hall, and the Fundamental Symmetries, Neutrons, and Neutrinos LRP Town Hall communities