Science

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Although most cancer drugs modulate the activities of cellular pathways by changing post-translational modifications (PTMs), surprisingly little is known regarding the extent and the time- and dose-response characteristics of drug-regulated PTMs. Here, we introduce a proteomic assay termed decryptM that quantifies drug-PTM modulation for thousands of PTMs in cells to shed light on target engagement and drug mechanism of action (MoA). Examples range from detecting DNA damage by chemotherapeutics, to identifying drug-specific PTM signatures of kinase inhibitors, to demonstrating that rituximab kills CD20-positive B-cells by over-activating B cell receptor signaling...

Venus has a geologically young surface, but it is unknown whether it has ongoing active volcanism. From 1990 to 1992, the Magellan spacecraft imaged the planet's surface using synthetic aperture radar. We examine volcanic areas on Venus that were imaged two or three times by Magellan and identify a ~2.2 km2 volcanic vent that changed shape in the eight months between two radar images. Additional volcanic flows downhill from the vent are visible in the second epoch images, though we cannot rule out that they were present but invisible in the first epoch due to differences in imaging geometry...

In addition to the conserved RNA polymerases (Pols) I-III in eukaryotes, two atypical polymerases, Pols IV and V, specifically produce non-coding RNA in the RNA-directed DNA methylation (RdDM) pathway in plants. Here, we report on the structures of cauliflower Pol V in the free and elongation conformations. A conserved tyrosine residue of NRPE2 stacks with a dsDNA branch of the transcription bubble to potentially attenuate elongation by inducing transcription stalling. The non-template DNA strand is captured by NRPE2 to enhance backtracking, thereby increasing 3'-5' cleavage which likely underpins Pol V's high fidelity...

Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many via engagement with more than 40 GPCRs. Searching for receptors to sense beneficial ω-3 FAs of fish oil enabled the identification of GPR120, involving with a spectrum of metabolic diseases. Here, we report six cryo-EM structures of GPR120 in complex with FA hormones or TUG891 and Gi or Giq trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling...

No abstract text is available yet for this article.

Transient sexual experiences can have long-lasting effects on behavioral decisions, but the neural coding that accounts for this change is unclear. We found that ejaculation experience selectively activated estrogen receptor 2 ( Esr2 )-expressing neurons in the bed nucleus of the stria terminalis (BNST)-BNSTEsr2 -and led to persistent decreases in firing threshold for days, during which time the mice displayed sexual satiety. Inhibition of hyperexcited BNSTEsr2 elicited fast mating recovery in satiated mice of both sexes...

Certain Inhibitors of apoptosis (IAP) family members are sentinel proteins preventing untimely cell death by inhibiting caspases. Antagonists including second mitochondria-derived activator of caspase (SMAC) regulate IAPs, driving cell death. Baculoviral IAP repeat-containing protein 6 (BIRC6), a giant IAP with dual E2/E3 ubiquitin ligase activity, regulates programmed cell death through unknown mechanisms. We show BIRC6 directly restricts executioner caspases-3 and -7, and ubiquitinates caspases-3, -7 and -9 working exclusively with non-canonical E1, UBA6...

Inhibitor of apoptosis proteins (IAPs) bind to pro-apoptotic proteases, keeping them inactive and preventing cell death. The atypical ubiquitin ligase BIRC6 is the only essential IAP, additionally functioning as a suppressor of autophagy. We performed a structure-function analysis of BIRC6 in complex with caspase-9, HTRA2, SMAC, and LC3B which are critical apoptosis and autophagy proteins. Cryo-electron microscopy structures show that BIRC6 forms a megadalton crescent shape that arcs around a spacious cavity containing receptor sites for client proteins...

Tight regulation of apoptosis is essential for metazoan development and prevents diseases such as cancer and neurodegeneration. Caspase activation is central to apoptosis and inhibitor of apoptosis (IAP) proteins are the principal actors that restrain caspase activity and are therefore attractive therapeutic targets. IAPs, in turn, are regulated by mitochondria-derived pro-apoptotic factors such as Smac and HtrA2. Through a series of cryo-electron microscopy (cryo-EM) structures of full-length human baculoviral IAP repeat-containing protein 6 (BIRC6) bound to Smac, caspases, and HtrA2, we provide a molecular understanding for BIRC6-mediated caspase inhibition and its release by Smac...

No abstract text is available yet for this article.

N 6 -methyladenosine (m6 A) is the most abundant mRNA modification and plays crucial roles in diverse physiological processes. Utilizing a Massively Parallel Assay for m6 A (MPm6 A), we discover that m6 A specificity is globally regulated by "suppressors" that prevent m6 A deposition in unmethylated transcriptome regions. We identify Exon Junction Complexes (EJCs) as m6 A suppressors that protect exon junction-proximal RNA within coding sequences from methylation and regulate mRNA stability through m6 A suppression...

Photoredox catalysis enables unique and broadly applicable chemical reactions but controlling their selectivity has proven to be difficult. The pursuit of enantioselectivity is a particularly daunting challenge, arguably due to the high energy of the activated radical (ion) intermediates, and previous approaches have invariably required pairing of the photoredox catalytic cycle with an additional activation mode for asymmetric induction. A potential solution for photoredox reactions proceeding via radical ions would be catalytic pairing with enantiopure counterions...

The deep magmatic architecture of the Hawaiian volcanic system is central to understanding the transport of magma from the upper mantle to the individual volcanoes. We leverage advances in earthquake monitoring with deep learning algorithms to image the structures underlying a major mantle earthquake swarm of nearly 200,000 events that rapidly accelerated following the 2018 Kīlauea caldera collapse. At depths of 36-43 km, we resolve a 15 km long collection of near-horizontal sheeted structures that we identify as a sill complex...

A magma network may feed into different volcanoes, including Mauna Loa and Kīlauea.

America's science, technology, and innovation ecosystem is a powerful engine for progress, but it was conceived in the last century for last century's goals. Today, the nation's aspirations have never been bigger: robust health and ample opportunity for everyone, tackling the climate crisis and using it to reimagine infrastructure and humanity's relationship with nature, global security and stability, a competitive economy that creates good-paying jobs, and a strong, thriving democracy. The purpose of science and technology is to open the doors that make these aspirations possible...

This dichotomy can inform environmental cooperation.

Neurotechnologies necessitate new thinking on human rights.

Structural analysis reveals how the decision to induce apoptotic cell death is regulated.

Recent advances in machine learning have leveraged evolutionary information in multiple sequence alignments to predict protein structure. We demonstrate direct inference of full atomic-level protein structure from primary sequence using a large language model. As language models of protein sequences are scaled up to 15 billion parameters, an atomic-resolution picture of protein structure emerges in the learned representations. This results in an order-of-magnitude acceleration of high-resolution structure prediction, which enables large-scale structural characterization of metagenomic proteins...