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Discovery of macrocyclic ligands to the 19S regulatory particle protein PSMD2 enables the synthesis of heterobifunctional molecules that demonstrate proof-of-concept, targeted degradation of BRD4 through direct engagement of the 26S proteasome.
This article presents a synthetic genetic program for orthogonal, tunable and programmable control of bacterial lifestyle and associated phase-specific gene expression, offering a versatile platform for microbial engineering in complex contexts.
The specificity constant of a promiscuous enzyme was raised by over 1,000-fold by using computational protein design to place a substrate recruitment domain adjacent to the enzyme active site.
A peptide display method was developed, revealing that a kinase important for infection by Salmonella and related pathogens detects specific human antimicrobial peptides, possibly reflecting bacterial adaptation to distinct host locations.
Anaplerotic reactions constantly refill metabolic networks with essential intermediates. This concept was adapted to enable a 54-step in vitro biosynthesis of the macrolide backbone of the antibiotic erythromycin from CO2.
The structure of SpoT assumes a compact τ-shaped structure in which the regulatory domains wrap around a core subdomain that controls the conformational state of the enzyme and primes it for (p)ppGpp hydrolysis.
Deep mutational scanning revealed the drug efflux activity profile of more than 1,430 single variants, enabling the identification of critical residues that regulate the activity of the bacterial drug efflux pump EfrCD in response to different drugs.
Cryo-EM structures of µ-opioid receptor complexes with two agonists coupled to molecular dynamics simulations and functional assays highlight distinct efficacy for G protein subtype activation and β-arrestin recruitment.
A membrane-tethering liquid–liquid phase-separation system was developed for programmable compartmentalization of cell-surface proteins and regulation of downstream cellular activities.
SEUSS is a transcriptional adaptor that undergoes condensation after hyperosmotic stress-induced increase of molecular crowding. The SEUSS condensates are indispensable for stress tolerance via facilitating the expression of stress-related genes.
The non-nucleoside reverse transcriptase inhibitors (NNRTIs) drive HIV protease-mediated CARD8 inflammasome activation, which is attenuated by dipeptidyl peptidase 9 (DPP9). DPP9 inhibitors act synergistically with NNRTIs to clear HIV-infected cells.
Coupling haploid genetics with deep scanning mutagenesis, Hanzl et al. identified functional hotspots in E3 ubiquitin ligases that are selectively required for different proteolysis-targeting chimeras (PROTACs) or molecular glue degraders and found mutated in relapsing patients.
Akizuki et al. reveal an unexpected role for K63-linked ubiquitin chains and the E2 enzyme UBE2N in degrader-induced degradation of cIAP1 through the proteasome, demonstrating the diversity of the ubiquitin code used for targeted degradation.
Coenzyme A (CoA) is a ubiquitous and essential cofactor. A biosensor for visualizing cytosolic and mitochondrial CoA in living cells was developed to address central questions concerning CoA homeostasis.
Velcrins kill cancer cells by inducing complex formation between PDE3A and SLFN12, upregulating SLFN12 RNase activity. Activated SLFN12 specifically cleaves tRNALeu(TAA), resulting in global inhibition of protein synthesis.
Fan et al. report a potent and subtype-selective TRPV3 antagonist, Trpvicin, and reveal its binding sites and mode of action for TRPV3 inhibition via high-resolution cryogenic electron microscopy structures.
The cryo-EM structures of MRGPRX1–Gq complexes are reported, which revealed the activation and allosteric modulation mechanism of human MRGPRX1 receptor, which may enable the structure-based identification of novel analgesics.
Murray et al. identified and characterized a small-molecule inhibitor of human COQ8A, which belongs to the UbiB protein family and is essential for coenzyme Q biosynthesis.