Volume 19 Issue 4, April 2023

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.

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.

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.

A modular platform was developed to generate designer condensates with tunable material properties for selective partitioning. These programmable assemblies can regulate bacterial plasmid expression and inheritance but will find a broad array of applications, including in eukaryote systems.

A new review article details how new structural insight regarding modular polyketide synthases (PKSs) helps us better understand the organization of catalytic events within a PKS module. The plausible models discussed will likely influence future PKS engineering efforts.

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.

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.

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.

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.

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.

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.

Guo et al. report a small molecule agonist of mitochondrial fusion that activates MFN1, an outer mitochondrial membrane protein, and protects cells from mitochondrial damage and ischemia/reperfusion injury in a mouse model.

Development of two bright light-up RNA systems with strong aptamer–dye interaction, high fluorogenicity, and remarkable photostability, enable single-molecule mRNA tracking in live cells.

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 multistep incorporation process of the catalytic NiFe(CN)₂(CO) cofactor into [NiFe]-hydrogenase was deciphered by isolating key maturation intermediates, which were characterized by biochemical and a variety of spectroscopic techniques.

Mercaptopyruvate sulfur transferase (MPST) is revealed as a protein persulfidase that acts directly on numerous and diverse target proteins, revealing potential origins of persulfidation as a common posttranslational modification.

Dai et al. present a streamlined approach for the design and engineering of synthetic biomolecular condensates for controlling different cellular processes, such as gene flow, transcriptional regulation and modulation of protein circuits.