Nature Chemical Biology

14h

Our November issue is live! www.nature.com/nchembio/vol... The cover image depicts the common midwife toad. Comparative peptidomics is used to reveal disease dynamics and variation in host AMP defenses to understand how toad populations can survive disease outbreak.

nature.comChemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells - Nature Chemical BiologyThe chemogenetic tool Grubraw activates mitochondria by generating pyruvate in the mitochondrial matrix. This triggers a genetic switch that slows down tumor cell proliferation. Tumor cells counteract...

Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells www.nature.com/articles/s41...

nature.comTryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1–HSPA9 complex - Nature Chemical BiologyDiversification distal to the electrophile profoundly alters the protein interaction landscape of covalent stereoprobes, revealing GRPEL1–HSPA9 disruptors and nonorthosteric liganding events missed by...

Diversification distal to the electrophile of covalent stereoprobes alters their protein interaction landscape, revealing GRPEL1-HSPA9 disruptors and nonorthosteric liganding events missed by cofolding models www.nature.com/articles/s41...

nature.comSingle Staphylococcus aureus SauUSI restriction enzyme motors fragment methylated DNA - Nature Chemical BiologyUsing single-molecule physics and biochemical assays, Shaw, Hughes-Games and Torres Montaguth et al. reveal how the bacterial defense enzyme SauUSI repeatedly scans and makes multiple DNA breaks, effi...

A new paper reveals how the bacterial defense enzyme S. aureus USI repeatedly scans and makes multiple DNA breaks, efficiently fragmenting invading genetic material www.nature.com/articles/s41...

nature.comA selective NVL inhibitor suppresses tumor growth by targeting ribosome biogenesis - Nature Chemical BiologyGuo, Tao and Cruz et al. identified a selective inhibitor named MM17 of nuclear valosin-containing protein-like (NVL), an AAA+ ATPase responsible for assembly of large ribosome subunit (60S). A bioava...

A selective NVL inhibitor suppresses tumor growth by targeting ribosome biogenesis www.nature.com/articles/s41...

nature.comPUS7 pseudouridylation of 7SK orchestrates human somatic cell reprogramming into iPS cells - Nature Chemical BiologyPUS7 promotes pluripotency through modification of the noncoding RNA, 7SK, enhancing its interaction with the BRG/BRM-associated factor complex. Replacing exogenous OCT4 with PUS7 generates induced pl...

PUS7 pseudouridylation of noncoding RNA 7SK orchestrates human somatic cell reprogramming into iPS cells www.nature.com/articles/s41...

nature.comProteome-guided drug discovery maps and mitigates therapeutic degrader toxicity - Nature Chemical BiologySystematic proteomic profiling uncovered mechanisms driving drug toxicity informing the design of safer and more effective protein degraders for the treatment of prostate cancer.

Proteome-guided drug discovery maps and mitigates therapeutic degrader toxicity www.nature.com/articles/s41...

nature.comHigh-resolution NMR spectroscopy of proteins in intact mitochondria - Nature Chemical BiologyAn approach has been developed for NMR observation of proteins within intact mitochondria through delivery of proteins directly into isolated mitochondria via electroporation. This method offers a fra...

High-resolution NMR spectroscopy of proteins in intact mitochondria www.nature.com/articles/s41...

nature.comDHODH is the key target of the KDM4 inhibitor QC6352 in glioblastoma stem cells - Nature Chemical BiologyQC6352, originally developed as a KDM4 inhibitor, exerts its anticancer activity in glioblastoma models primarily through inhibition of dihydroorotate dehydrogenase, a key enzyme in de novo pyrimidine...

QC6352, originally developed as a KDM4 inhibitor, exerts its anticancer activity in glioblastoma models primarily through inhibition of DHODH, a key enzyme in de novo pyrimidine biosynthesis www.nature.com/articles/s41...

nature.comCell-cycle-driven noncanonical ubiquitination of METTL14 orchestrates RNA methylation - Nature Chemical BiologyCao, Ying, Zhou, Zhang and colleagues identified a CDK1/cyclin B1–RLIM–METTL14 axis that couples the cell cycle to mRNA m6A dynamics through periodic RLIM-mediated K27-linked ubiquitination on methylt...

Cell-cycle-driven noncanonical ubiquitination of METTL14 orchestrates RNA methylation www.nature.com/articles/s41...

nature.comTranscription remodeling and stalling by cisplatin-induced interstrand crosslinks - Nature Chemical BiologyBy solving the cryo-electron microscopy structures of cisplatin-induced DNA interstrand crosslinks (ICLs) in complex with RNA polymerase II, Zhu, Zhao and colleagues reveal how RNA polymerase II remod...

Cryo-EM structures of RNA polymerase II (Pol II) with cisplatin-induced DNA interstrand crosslinks (ICLs) reveal how Pol II remodels cisplatin-ICLs, stalls transcription, and commits lesions to transcription-coupled repair www.nature.com/articles/s41...

nature.comMultiomic proximity labeling in vivo by D-amino-acid-activated peroxidase reaction - Nature Chemical BiologyA nontoxic proximity labeling approach is developed using an engineered D-amino acid oxidase and APEX2 fusion to generate H2O2 in situ from D-amino acids. It is applied in vivo in Caenorhabditis elega...

A nontoxic proximity labeling method generating H2O2 in situ from D-amino acids enables protein and RNA proximity labeling and mapping RNA structural changes in vitro and in vivo www.nature.com/articles/s41...

nature.comSRSF1 modulates the dark nucleolar cap pH to restore nucleolar integrity and function - Nature Chemical BiologyThis study finds that SRSF1, a nuclear speckle-resident splicing factor, modulates the pH microenvironment in the dark nucleolar caps through its intrinsic positive charge, thereby ensuring nucleolar ...

SRSF1 modulates the dark nucleolar cap pH to restore nucleolar integrity and function www.nature.com/articles/s41...

nature.comHalting translation by the letter with sequence-selective small molecules - Nature Chemical BiologySmall-molecule modulators of protein synthesis are invaluable tools for dissecting the translation apparatus. This Review summarizes the mechanisms of molecules that disrupt translation in an amino ac...

A new Review highlights the mechanisms of molecules that disrupt translation in an amino acid or mRNA sequence-dependent manner www.nature.com/articles/s41...

Our October issue is live! www.nature.com/nchembio/vol... Inspired by the phases of the moon, the cover artwork uses light and darkness to depict pharmacological control of chimeric antigen receptor (CAR) T cells

nature.comBiosynthetic allene and alkyne formation by enzymatic prenyl demethylation - Nature Chemical BiologyAllenes and alkynes are important functional groups in chemical biology, yet their biosynthesis is poorly understood. Now, Liu et al. reveal that they form via oxidative C(sp2)-demethylation of the pr...

18 Sept

Allenes and alkynes can be biosynthesized via oxidative C(sp2)-demethylation of a prenyl group by fungal cytochrome P450s, expanding the catalytic repertoire of P450 enzymes www.nature.com/articles/s41...

Nature Chemical Biology reposted

Drug Discovery Unit, University of Dundee

@ddu-dundee.bsky.social

17 Sept

Happy New Paper Day! We're excited to share this @natchembio.nature.com on #SmallMoleculeInhibitors of NorA, an efflux pump that is an important mediator of #antibioticresistance in #MRSA. It pumps antibiotics out , lowering their concentration in the cell. doi.org/10.1038/s415...

doi.orgSmall-molecule inhibitors block NorA efflux by conformational trapping - Nature Chemical BiologyMultidrug efflux pumps expel antibiotics, contributing to antibiotic resistance. Now, high-throughput screening and structural characterization reveal an inhibitor of Staphylococcus aureus efflux pump...

nature.comPyridoxal-phosphate-dependent biosynthesis of aminovaleramide by AvaS in tRNA - Nature Chemical BiologySun, Wu et al. identify AvaS as a pyridoxal-phosphate-dependent RNA-modifying enzyme, producing the tRNA modification ava2C from k2C in bacteria and plants and linking RNA chemistry to translational r...

AvaS is a pyridoxal-phosphate-dependent RNA-modifying enzyme, producing the tRNA modification ava2C from k2C in bacteria and plants and linking RNA chemistry to translational regulation of metabolic stress responses www.nature.com/articles/s41...

nature.comA sequence motif enables widespread use of noncanonical redox cofactors in natural enzymes - Nature Chemical BiologyNoncanonical redox cofactors (NRCs) are promising alternatives to nicotinamide adenine dinucleotide (phosphate) (NAD(P)+) for biomanufacturing because of expanded capabilities and lower cost; however,...

A sequence motif enables widespread use of noncanonical redox cofactors in natural enzymes www.nature.com/articles/s41...

nature.comPlasma membrane order maps functional diversity in immune cells - Nature Chemical BiologyCells undergo membrane remodeling in response to the environment to perform specific functions. Now, a cytometry-based method with immune cell biomarker analysis captures variations in plasma membrane...

Plasma membrane order maps functional diversity in immune cells www.nature.com/articles/s41...

nature.comChemogenomic maps reveal a PRDX1-dependent iron–damage axis in the DNA damage response - Nature Chemical BiologyLarge-scale CRISPR dependency mapping reveals 1,000+ genes that modify cellular outcomes to DNA damage response drugs. Loss of PRDX1, acting through a PAX7–MRGBP–IREB2 pathway, broadly sensitized cell...

Chemogenomic maps reveal a PRDX1-dependent iron-damage axis in the DNA damage response www.nature.com/articles/s41...

nature.comMacrophages transfer functional proteins to their surface during live-cell uptake - Nature Chemical BiologyMacrophages acquire intact surface proteins from cancer cells during live-cell uptake, with these proteins remaining active, revealing a transcriptionally silent process where macrophages can reengine...

Macrophages transfer functional proteins to their surface during live-cell uptake www.nature.com/articles/s41...

nature.comDirected evolution of Lantern enables rapid RNA and protein proximity labeling - Nature Chemical BiologyFang, Ren, Zheng, Wang et al. developed Lantern, a variant of miniSOG, through directed evolution for subcellular transcriptomes and proteomes analyses inside living cells, enabling findings that RNA ...

Directed evolution of Lantern enables rapid RNA and protein proximity labeling www.nature.com/articles/s41...

nature.comMechanism of the M. tuberculosis DprE1–DprE2 epimerase complex and inhibition by anti-tubercular drugs - Nature Chemical BiologyPretomanid and delamanid are prodrugs reported to target the decaprenylphosphoribose-2′-reductase DprE2, while the noncovalent inhibitor quabodepistat has been reported to target the decaprenylphospho...

2 Sept

Mechanism of the Mtb DprE1-DprE2 epimerase complex involved in cell wall synthesis and inhibition by anti-tubercular drugs www.nature.com/articles/s41...

nature.comα2,6-Sialoglycan-regulated antitumor immunity of tumor-infiltrating CD8+ T cells - Nature Chemical BiologyAlthough hypersialylation on cancer cells and its roles in immune evasion and metastasis are well known, the functional roles of cell-surface sialylation on tumor-infiltrating immune cells (TIICs) are...

α2,3- or α2,6-sialoglycan linkage-specific barcoding is developed and, combined with scRNA-seq, reveals differential regulation and function of α2,3- and α2,6-sialylation in subpopulations of tumor-infiltrating immune cells www.nature.com/articles/s41...

nature.comAn enantioselective covalent inhibitor of BAX confers cytoprotection in vivo - Nature Chemical BiologyAn enantioselective covalent inhibitor was developed that restrains BAX, protecting mouse liver and human motor neurons from injury and establishing covalent BAX inhibition as a promising strategy to ...

An enantioselective covalent inhibitor of BAX constrains BAX conformation and suppresses pathological cell death in mouse liver and human motor neurons www.nature.com/articles/s41...

A new Perspective by Changhao He and Kevan Shokat on the adaptive mechanisms and emerging chancer therapeutics for CDK2 inhibitors www.nature.com/articles/s41...

Our September issue is live! www.nature.com/nchembio/vol... The cover image depicts the localization of MESH1 (green) to the Golgi (red and yellow). MESH1 is identified to regulate the availability of the universal biological sulfate donor PAPS.

nature.comCA-IV-directed small-molecule shuttle enables targeted brain delivery of biologics - Nature Chemical BiologyExisting receptor targets to direct delivery of biologics across the blood−brain barrier are ubiquitously expressed in the central nervous system (CNS) and peripheral tissues. Now, carbonic anhydrase ...

27 Aug

Targeted brain delivery of biologics through conjugation of a small molecule targeting a brain-enriched receptor, carbonic anhydrase IV (CA-IV) www.nature.com/articles/s41...

nature.comTopogenic sequence recognition at TIM complexes revealed by a stendomycin-bound structure - Nature Chemical BiologyThe mitochondrial inner membrane complexes TIM23 and TIM22 mediate distinct protein topogenesis functions in polypeptide import. The authors reveal their mechanistic overlap in topogenic sequence reco...

27 Aug

A new paper reveals the mechanisms of topogenic sequence recognition in mitochondrial inner membrane complexes TIM23 and TIM22 www.nature.com/articles/s41...

nature.comEntering the agentic era of AI in drug discovery - Nature Chemical BiologyAgentic AI systems are reshaping drug discovery, and the convergence of agentic AI with laboratory automation is enabling the design of self-driving laboratories that transform the design–make–test–an...

27 Aug

A new Comment discusses the advances and potential of agentic AI systems in drug discovery www.nature.com/articles/s41...

Nature Chemical Biology reposted

Jin Zhang Lab

@jinzhanglab.bsky.social

24 Aug

📢 Thrilled to share our new publication in @natchembio.nature.com, led by our former graduate student Ryan Weeks! In this work, we develop HaloRasAR, a chemigenetic biosensor capable of detecting endogenous Ras by fluorogenic increase in far-red fluorescence. Find out more in the paper!

nature.comA chemigenetic endogenous Ras activity biosensor for live-cell pharmacology - Nature Chemical BiologyHere the authors present a biosensor for measuring endogenous Ras in live cells, based on HaloTag and the fluorogenic JF635 dye, and they use it to report location-specific inhibition profiles of dist...

ryan weeks@ryanweeeeks.bsky.social

Really excited to share the publication of my PhD work in the Jin Zhang lab at UCSD! You can find it here in Nature Chemical Biology. www.nature.com/articles/s41...

nature.comLiving circuit boards built by printing bacterial transistors - Nature Chemical BiologyElectronic circuit boards carry out different operations on the basis of the configuration of their components. Now, equivalent biological circuits are engineered that compute functions on the basis o...

17 Aug

Biological circuit boards are engineered that compute functions based on the spatial arrangement of different bacterial strains printed on a surface www.nature.com/articles/s41...

nature.comPhotoproximity labeling of c-Myc reveals SLK as a cancer-specific co-regulator - Nature Chemical BiologyA photoproximity-labeling approach maps cancer-specific partners of the c-Myc oncoprotein, revealing that the kinase SLK binds and stabilizes c-Myc, drives tumor growth and offers a new strategy to ta...

17 Aug

Photoproximity labeling of c-Myc reveals SLK as a cancer-specific co-regulator www.nature.com/articles/s41...

nature.comBrønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants - Nature Chemical BiologyThrough chemical complementation, Brønsted-basic small molecules rescue the loss of the catalytic glutamine side chain in KRAS-Q61X mutants, accelerating GTP hydrolysis up to 20-fold.

Bronsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants www.nature.com/articles/s41...

nature.comMetabolic reprogramming drives pancreatic β cell neogenesis from α cells - Nature Chemical BiologyA chemical screen identified a PRC2–AR–ETV1–PPP axis that regulates β cell identity features in α cells. An intermediate PPP metabolite, methyl esterified 6-phosphogluconate, induced metabolic reprogr...

A chemical screen identifies a PRC2-AR-ETV1-PPP axis that regulates pancreatic β cell identity features in α cells. An intermediate PPP metabolite induces metabolic reprogramming to stimulate β cell regeneration www.nature.com/articles/s41...

nature.comA covalent PFKL activator suppresses tumor growth - Nature Chemical BiologyAn electrophile–drug conjugate covalently activates PFKL through K677 engagement and releases a selective CPT2-targeting payload. This strategy exploits metabolic vulnerabilities to suppress tumor gro...

A covalent PFKL activator suppresses tumor growth www.nature.com/articles/s41...

nature.comBlack yeasts are efficient heterologous hosts for the production of a wide range of fungal polyketides - Nature Chemical BiologyHere, the authors establish and validate two black yeasts as heterologous hosts for fungal polyketide discovery and production, combining the metabolic robustness of filamentous Aspergillus species wi...

Black yeasts are efficient heterologous hosts for the production of a wide range of fungal polyketides www.nature.com/articles/s41...

Nature Chemical Biology reposted

Pedro Friedmann Angeli

@angelifriedmann.bsky.social

6 Aug

Hi, some news from the group! Fresh review in @natchembio.nature.com discussing tools and analytics for the study of #selenium :-) www.nature.com/articles/s41...

nature.comEmerging tools to investigate the contribution of selenium to ferroptosis and beyond - Nature Chemical BiologyThis Review examines the chemical complexity of selenium biology and the tools available to study it. Defining current limitations in detecting selenium species outlines pathways toward a more precise...

Nature Chemical Biology reposted

César de la Fuente

@delafuentelab.bsky.social

3 Aug

Published today in @natchembio.nature.com @natureportfolio.nature.com: a framework for the de novo design of antimicrobial α-helical peptides that assemble into transmembrane barrel-stave nanopores.

nature.comExpanding the repertoire of chemically induced covalent neoantigens - Nature Chemical BiologySmall molecules can covalently modify proteins to generate hapten-modified peptides, triggering T cell-mediated immune responses. Now a chemoproteomic platform enables the discovery of covalent neoant...

31 July

Small molecules can covalently modify proteins and generate covalent neoantigens, triggering immune responses. Now, a chemoproteomic platform enables the discovery of covalent neoantigens, which can also be harnessed for immunotherapeutic applications www.nature.com/articles/s41...

30 July

Check out our Editorial “Computing complexity” which refers to both modeling biological complexity and the computational challenges www.nature.com/articles/s41...

Nature Chemical Biology@natchembio.nature.com

Our August issue is live and is a Focus on computational work guiding biological discovery! www.nature.com/nchembio/vol... The cover image depicts a computational-experimental approach to distinguish lipid solvation vs. lipid-ligand binding in membrane protein function

30 July

nature.comDesigning fiber–gut microbiome interactions with active learning - Nature Chemical BiologyDietary fibers are a primary energy source for gut bacteria and shape the composition and function of the microbiome. Now, an active learning approach integrating explainable machine learning, Bayesia...

28 July

An active learning approach integrating explainable machine learning, Bayesian optimization, and high-throughput community construction designs microbial communities with desired functions in response to key nutrients www.nature.com/articles/s41...

nature.comAI design of gut microbiomes - Nature Chemical BiologyThe gut microbiome converts dietary fiber into metabolites that shape human health, but identifying the right combinations of microorganisms and nutrients has been a challenge. A machine learning fram...

28 July

AI design of gut microbiomes – Check out the associated News & Views by Daniel Ferrer, Mark Holton, and Guillaume Urtecho www.nature.com/articles/s41...

nature.comUsing enantioselective biosensors to evolve asymmetric biocatalysts - Nature Chemical BiologyHere d’Oelsnitz et al. generate enantioselective transcription factors that convert chiral reaction products into fluorescent signals, enabling the rapid evolution of asymmetric enzymes with inverted ...

28 July

Enantioselective transcription factors are evolved that convert chiral reaction products into fluorescent signals, enabling the screening and evolution of asymmetric enzymes with inverted selectivity www.nature.com/articles/s41...

nature.comRestoring intracellular homeostasis disrupted by synthetic nanoassemblies - Nature Chemical BiologyCells have evolved defense pathways to maintain homeostasis against external perturbations, but not against new-to-nature nanomaterials, which can irreversibly accumulate and induce cell stress. Now, ...

17 July

New-to-nature nanomaterials can irreversibly accumulate in cells and induce cell stress. Now, peptide assemblies have been designed that morphologically transform in influx-efflux cycles in response to restoring redox homeostasis in bacterial cells www.nature.com/articles/s41...

nature.comEarly maturation of host antimicrobial peptide defences is associated with host–pathogen coexistence - Nature Chemical BiologyHost antimicrobial peptides (AMPs) are a frontline defense against infection. Now, it has been shown that maturation of AMP repertoires early in life can predict stable host coexistence with a highly ...

17 July

Host antimicrobial peptides (AMPs) are a frontline defense against infection. A new paper shows maturation of AMP repertoires early in life can predict stable coexistence with a highly invasive pathogen www.nature.com/articles/s41...

nature.comProteoform-specific enrichment of phosphopeptide isomers by polymer-based synthetic receptors - Nature Chemical BiologyResolution of protein phosphorylation at specific sites is challenging. Now, synthetic receptors have been developed that enable high-resolution enrichment of ultralow-abundance phosphopeptide positio...

14 July

Synthetic receptors enable high-resolution enrichment of ultralow-abundance phosphopeptide positional isomers from complex human proteomes www.nature.com/articles/s41...