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The androgen receptor forms nuclear condensates associated with gene transcription. Investigating the molecular basis of condensate formation led us to discover an approach for optimizing small molecules that inhibit the receptor in a currently untreatable form of prostate cancer.
In this Review, the authors discuss the various ways that alternative splicing sculpts the landscape of protein interactions with their partners, essentially all types of biomolecules, and the implications of alternative interactions at the molecular, cellular and disease level.
We describe how transcription start site (TSS) choice of thousands of genes results in transcript isoforms with potential for distinct post-transcriptional regulation affecting translation and cell behavior. We show that dynamic switching between initiation sites defines cancer proliferation, differentiation and treatment response, indicating start site determination as a potential diagnostic tool.
An Ago2HA/HA mouse model combined with super-resolution microscopy, molecular and biochemical assays allowed us to stringently characterize AGO2 regulation in vivo. We found that in quiescent splenocytes, AGO2 localizes almost exclusively to the nucleus, where it binds to the RNA of young mobile transposons and represses their expression through its catalytic domain.
The human ATPase p97 (also known as VCP) unfolds protein substrates by translocating them through its central channel. This process is highly regulated by numerous adapter proteins. Structures of p97 in complex with the unusual adapter UBXD1 reveal how this protein coordinates p97 hexamer remodeling and ring opening by expansive interactions across multiple p97 protomers.
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.
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.
Cells maintain homeostasis under stress conditions by minimizing damages, maintaining structural integrity and modifying the activity of macromolecules and signaling molecules such as kinases and phosphatases. Though a comprehensive view of how stress-regulated signaling pathways regulate cell survival remains elusive, new work sheds some light.
The Review provides an overview of ion-channel insecticide targets, with a focus on their mechanisms of action, and offers a perspective for structure-based development of insecticides.
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.
The release of inorganic phosphate (Pi) 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 Pi through a ‘molecular backdoor’ and demonstrate that this arrangement is distorted in a disease-linked actin variant.
The microtubule motor dynein is regulated by lissencephaly-1 (Lis1) at several points during its complex activation process. Two papers reveal the molecular mechanism for two steps: the beginning, when Lis1 acts as a wedge to disrupt dynein’s autoinhibited conformation; and the end, when microtubule binding ejects Lis1 from the motor.
New cryo-electron microscopy (cryo-EM) structures of CDP- and CDP-choline-bound choline phosphotransferase 1 (CHPT1) and choline/ethanolamine phosphotransferase 1 (CEPT1), involved in the metabolism of the two main lipids in eukaryotic cell membranes, capture the membrane proteins at resolution <4 Å, sufficient to gain mechanistic insights into these enzymes.
The development of an epigenetics-focused, CRISPR-based high-content functional genomics screening platform provides insight into chromatin regulation and uncovers a potential strategy to treat an aggressive type of leukemia.
In vitro reconstitution of recognition of 80S ribosomes by CCR4–NOT, cryo-electron microscopy (cryoEM), crosslinking mass spectrometry and biochemical characterization reveal that CCR4–NOT specifically identifies ribosomes stalled during translation elongation. CCR4–NOT occupies the ribosomal exit site (E site) and locks the ribosomal L1 stalk in an open conformation to enforce the stalled state.
New work shows that in mammals, the iDDR motif of telomere factor TRF2 inhibits the MRE11–RAD50–NBS1 (MRN) complex at chromosome ends through a direct iDDR–RAD50 interaction. Unrelated protein motifs in yeasts inhibit MRN functions via an analogous mechanism, suggesting a convergent evolution in eukaryotes to control MRN action at telomeres.
Here we report Droplet Paired-Tag, a rapid and robust method to simultaneously profile histone modifications and gene expression in single cells at scale. The new procedure provides researchers with a tool for studying the epigenome and gene regulation in complex tissues and disease pathogenesis.
