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Small-molecule-mediated targeted protein degradation (TPD) relies on the recruitment of a target protein of interest to an E3 ligase. A new study indicates how direct target recruitment to the 26S proteasome can bypass this requirement.
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.
Most engineered bacteria are designed to grow and function in a free-swimming state. A new method enables engineered bacteria to reversibly transition into a biofilm state.
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.
A protein–protein interface between a peptide-recognition domain (Fyn-SH3) and catechol O-methyltransferase (COMT) is computationally designed to generate a highly selective peptide-modifying system. Detailed mechanistic analysis sets a gold standard for studying the complex kinetic properties of designer fusion proteins.
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.
Inspired by nature, a synthetic carbon fixation cycle builds complex molecules directly from CO2. Building metabolism from the ground up requires several innovative advancements — now, a strategy to balance carbon demands in a complex metabolic network is explored.
Bacteria utilize stringent factors to metabolize the nucleotide alarmone guanosine tetra-/pentaphosphate, or (p)ppGpp, for stress adaptation. Now, a distinct conformation of these factors explaining their regulation and specialization has been unveiled.
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.
Major hurdles remain in understanding the mechanisms of multidrug resistance (MDR) protein efflux. A new study uses deep mutational scanning of a bacterial MDR protein to determine the nature of its drug-binding cavity and understand its function and plasticity.
High-mannose N-glycans are common post-translational modifications that occur on many proteins. The mechanism by which these high-mannose N-glycans are consumed by species of Bifidobacterium has now been characterized, which is important given their positive role in human gut microbiota and their abundance in breastfed infants.
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.
