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The kinesin-1 motor protein accesses open active and closed autoinhibited states. These states are regulated by a flexible elbow within a complex coiled-coil architecture. Now, a conformational switch has been developed by engineering the elbow to create a closed state that can be controllably opened with a de novo designed peptide to increase kinesin transport inside cells.
Fluorogenic RNA aptamers have previously been developed to enhance RNA imaging. We determined the tertiary complex structures of a newly discovered Clivia aptamer, which exhibits a small size and a large Stokes shift. Structural insights into the fluorescence activation mechanism of Clivia build a strong foundation for its efficient use in RNA imaging.
Toxic small alarmone synthetase (toxSAS) enzymes are toxic effectors of certain toxin–antitoxin modules, involved in phage defense and secretion systems. Here the authors establish the mechanism underlying toxSAS inhibition by structured antitoxins and reveal the connection between neutralization strategy and substrate specificity.
To understand the complex dynamics and diverse functions of RNA, robust technologies for labeling and imaging RNA are highly desirable. A newly developed green fluorescent aptamer named Okra enables the imaging of mRNA dynamics in living cells.
Enediyne natural products are potent antitumor antibiotics but the biosynthesis of their 1,5-diyne-3-ene core has remained enigmatic for decades. Here a diiodotetrayne is reported as a universal enediyne biosynthetic intermediate of this core, obtained upon cryptic iodination.
A de novo-designed protein that precisely assembles a chlorophyll dimer has been developed. The design matches the conformation of the native ‘special pair’ of chlorophylls that functions as the primary electron donor in natural photosynthetic reaction centers. In the designed protein, excitonically coupled chlorophylls participate in energy transfer. The proteins were also redesigned to assemble into 24-chlorophyll nanocages.
We developed a rational approach to design peptide-based covalent inhibitors and coupled the inhibitors with antibodies for cell-specific delivery. We used this platform to generate antibody–peptide inhibitor conjugates (APICs) that target a family of proteases, the cysteine cathepsins. Our drug design and targeted delivery approach ensure specific inhibition and achieve therapeutic efficacy in different cancer cells and osteoclasts.
Jiang et al. developed a computational method to design repeat proteins with multiple structured loops that are buttressed by extensive hydrogen bond networks. The designs were further functionalized into high-affinity peptide-binding proteins.
Huang et al. report the tertiary structure of a small monomeric fluorogenic RNA aptamer named Clivia, characterized by a large Stokes shift, revealing the fluorescence activation mechanism and enabling a multivalent design to enhance the fluorescence output at specific dye concentrations.
Cathepsins are relevant therapeutic targets in cancer and other diseases. Here, the authors developed a different approach to block the activity of cathepsins in specific cellular contexts by combining non-natural peptide inhibitors with antibodies, enhancing therapeutic efficacy while reducing side effects.
The ZDHHC family of palmitoyl transferases lipidates numerous protein targets, but the paucity of selective inhibitors has hindered their target profiling. A generalized chemical genetic system can now map the protein targets of individual ZDHHC family members.
Targeted protein degradation has emerged as a promising approach in drug discovery, harnessing a cell’s intrinsic machinery to eliminate disease-related proteins. Now, a study paves the way to translating this technology into potential anti-mycobacterial therapies, by exploiting the bacterial protein-degradation complex.
Zuo et al. developed a highly bright and stable green fluorescent RNA for robust imaging of the dynamics of messenger RNA in living cells, enabling visualization of nonuniform and distinct distributions of different RNAs throughout stress granules.
Engineered living materials harness the computational power of biology to control interesting material properties. Here the authors leverage complex transcriptional regulation of bacterial extracellular electron transfer to control hydrogel cross-linking with Boolean logic.
Reliably identifying ubiquitin ligase interactors and substrates has been a persistent challenge in cellular biology. A breakthrough comes in the form of a potent, selective and cell-active chemical probe, shedding light on the intricate functions of a key regulatory enzyme.
Owens et al. reported PFI-7, a selective and potent antagonist of GID4 of the CTLH E3 ligase complex, which enables identification of human GID4 targets. This study provides valuable insights into GID4 functions and a powerful tool for advancing new targeted protein degradation strategies.
Yin et al. discover that the phosphatase PTENα acts as an RNA-binding protein, mitigating viral-induced inflammation in the brain by constraining RIG-I activation, suggesting PTENα as a potential therapeutic target for viral infection.