Volume 30 Issue 11, November 2023

The targeting and modulation of G-protein-coupled receptors (GPCRs) has immense therapeutic potential. A study in Nature now reports on the successful targeting of intracellular allosteric sites that effectively bias GPCR signaling, which has opened new opportunities to develop safer therapeutic agents.

OAT1 has a fundamental role in the kidney by facilitating the urinary excretion of various drugs and endogenous metabolites. Two studies now present high-resolution structures of OAT1 using cryo-EM, elucidating its intricate polyspecific transport capabilities and paving the way for structure-based drug research and development.

Ferroptosis suppressor protein 1 (FSP1, or AIFM2), an NADPH quinone reductase noted to protect cancer cells from ferroptosis, acts in FAD/NADPH binding and proton transfer. Recent papers assess its evolutionarily conserved sites via mutagenesis and define its inhibition as an off-target mediator of brequinar-mediated ferroptosis sensitization.

The release of inorganic phosphate (P_i) from actin marks old actin filaments for disassembly. By combining cryo-electron microscopy (cryo-EM) with in vitro reconstitution and molecular dynamics simulations, we show how actin filaments release P_i through a ‘molecular backdoor’ and demonstrate that this arrangement is distorted in a disease-linked actin variant.

This study revealed the mechanism by which the E3 ligase Bre1 directs monoubiquitination of histone H2B at K123 by the E2 ubiquitin-conjugating enzyme Rad6. Comparison with other dimeric E3 ligases suggests a pivot-like mechanism in which one subunit ‘tunes’ the specificity for particular histone residues.

This study describes an approach to segment and extract key biophysical parameters from live-cell three-dimensional single-molecule imaging trajectories. The authors use this approach to study how NuRD assembles on chromatin and how it regulates enhancer dynamics.

Here, the authors unveil the intrinsic ability of the C terminus of SSX, as part of different oncogenic fusions, to determine fusion occupancy independent of the BAF complex by both recognizing and stimulating histone H2AK119 monoubiquitylation by PRC1.1.

A family of large-genome bacteriophages assembles a protective protein shell around its replicating DNA called the ‘phage nucleus’. Here, Enustun et al. use proteomics to identify a set of proteins associated with the phage nucleus that aid macromolecule transport through the nuclear shell.

Here, using cryogenic electron microscopy and cryoDRGN, the authors delineate how the anaphase-promoting complex/cyclosome is reconfigurated to interact with its cognate E2s and thus polyubiquitinate its target. Unexpectedly, multiple ubiquitin moieties are shown to interact with the anaphase-promoting complex/cyclosome machinery, including its activator Cdh1.

Here, using cryo-EM, the authors show how Cas1–Cas2/3 and integration host factor, by means of a U-shaped bend that traps the invading DNA and a loop that positions it for the integrase, regulate integration of foreign DNA into the first repeat of the CRISPR array.

By obtaining structural snapshots of the catalytic cycle of NADH:quinone oxidoreductase from Vibrio cholerae, the authors uncover its mechanism. They show how electrons are shuttled and determine the importance of the [2Fe-2S] cluster in the movement of the electron transfer switch.

The authors present the full-length dimeric TRIM72 E3 ubiquitin ligase and the architecture of its high-order assembly bound to a phosphatidylserine-enriched membrane, providing insights into its role in membrane repair and ubiquitylation.

Here, using single-molecule experiments, the authors show that SpCas9 responds to shifted PAMs by inducing overhanging DNA ends. Such shift-PAM targeting is enhanced by physiological levels of DNA supercoiling and in turn promotes dissociation of the complex after catalysis.

Here, the authors show that PDHE1α accumulates at DNA double-strand breaks, in a PARylation-dependent manner, where it locally supplies acetyl-CoA for histone acetylation. These events facilitate remodeling of the chromatin landscape and efficient repair.

Reimer et al. used cryo-EM and cellular assays to reveal the structural and regulatory features that distinguish LRRK1 from LRRK2, and placed these features in the context of the evolution of the LRRK family of proteins.

The authors solved the cryo-EM structure of Myomaker, essential for myoblast fusion, and showed that it adopts a GPCR-like fold. They pinpointed the role of the dimeric interface and lipid-binding sites for fusion, and proposed a mechanism that may be conserved between species.

Here, the authors constructed a deep-learning approach to design closed repeat proteins with central binding pockets—a step towards designing proteins to specifically bind small molecules.

Here, the authors provide a comprehensive atlas of stress-responsive phosphorylation in yeast. Their unprecedentedly deep datasets allow them to showcase shared and divergent signaling events between stressors and to unveil functional organization principles.

Release of inorganic phosphate (P_i) from actin marks older actin filaments for disassembly. Here, the authors show how P_i exits the F-actin interior through a ‘molecular backdoor’. The backdoor arrangement is distorted in a disease-linked actin variant.

Organic anion transporter 1 (OAT1) structures reveal the molecular basis for the selective uptake and elimination of metabolites, drugs and toxins in the kidney.

Here the authors report the structures of OAT1, a drug transporter implicated in transporter-mediated drug interactions, unveiling the mechanism of its polyspecific substrate binding.

Extensive mutational analyses of ferroptosis suppressor protein-1 (FSP1) reveal its molecular mechanism in ferroptosis prevention and uncover the mechanism of action of the FSP1 inhibitor iFSP1 and a new species-independent FSP1 inhibitor, viFSP1.

Mao et al. reported ribosomal frameshifting events shortly after start codon selection, which is influenced by the sequence context and controlled by initiation factor eIF5B. This translational ‘noise’ is increased in response to nutrient starvation.