Featured
-
-
Article
| Open AccessDiscovery and biosynthesis of karnamicins as angiotensin converting enzyme inhibitors
Treatment of hypertension entails use of angiotensin-converting enzyme inhibitors. Here, the authors show a series of karnamicins with significant inhibitory activity and identify two unusual flavoprotein hydroxylases involved in the assembly of the fully-substituted hydroxypyridine core of karnamicins.
- Zhiyin Yu
- , Jian-Ping Huang
- & Sheng-Xiong Huang
-
Article
| Open AccessStructural basis of transcription recognition of a hydrophobic unnatural base pair by T7 RNA polymerase
T7 RNA polymerase (RNAP) is widely used for synthesizing RNA molecules with synthetic modifications and unnatural base pairs (UBPs). Here, authors show the structural basis of how UBPs are recognized as template and substrate, providing mechanistic insights into UBP transcription by T7 RNAP.
- Juntaek Oh
- , Michiko Kimoto
- & Dong Wang
-
Article
| Open AccessA specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression
This study describes RK-701, an inhibitor of histone methyltransferases G9a/GLP, as a promising therapeutic candidate for sickle cell disease and a universal role of BGLT3 lncRNA in fetal hemoglobin reactivation by chemical inducers including RK-701.
- Shohei Takase
- , Takashi Hiroyama
- & Akihiro Ito
-
Article
| Open AccessDeciphering the catalytic mechanism of superoxide dismutase activity of carbon dot nanozyme
Superoxide dismutase (SOD) nanozymes show mitigating effect on oxidative stress-related diseases, but are limited by their modest activity. Here, the authors report a carbon dot SOD nanozyme with catalytic activity matching natural enzymes and unveil its catalytic mechanism.
- Wenhui Gao
- , Jiuyang He
- & Xiyun Yan
-
Article
| Open AccessAdditive-controlled asymmetric iodocyclization enables enantioselective access to both α- and β-nucleosides
Nucleosides and their analogs are pharmacologically important molecules. Here, the authors report an additive-controlled stereodivergent iodocyclization method for the selective synthesis of α- or β-nucleosides.
- Qi Wang
- , Jiayi Mu
- & Fener Chen
-
Article
| Open AccessThermodynamic architecture and conformational plasticity of GPCRs
GPCRs are integral membrane proteins that serve as attractive drug targets. Here, authors delineate the conformational landscapes of 45 GPCRs using a statistical model, highlighting their malleable native ensembles and providing functional insights.
- Sathvik Anantakrishnan
- & Athi N. Naganathan
-
Article
| Open AccessLeveraging molecular structure and bioactivity with chemical language models for de novo drug design
Generative Deep Learning holds promise for mining the unexplored “chemical universe” for new drugs. Here, the authors demonstrate the de novo design of phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors for the PI3K/Akt pathway in human tumor cells.
- Michael Moret
- , Irene Pachon Angona
- & Gisbert Schneider
-
Article
| Open AccessTargeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation
Here the authors generate an RNA-based platform to neutralize the major epigenetic player DNMT1. Using this targeted approach, aberrant DNA methylation in cancer can be corrected.
- Carla L. Esposito
- , Ida Autiero
- & Annalisa Di Ruscio
-
Article
| Open AccessFilamin A organizes γ‑aminobutyric acid type B receptors at the plasma membrane
GABAB receptors mediate the effects of the main inhibitory neurotransmitter in the brain. Here, authors identify the cytoskeletal protein filamin A as a key player that controls the exact location and function of GABAB receptors at the cell surface.
- Marie-Lise Jobin
- , Sana Siddig
- & Davide Calebiro
-
Article
| Open AccessPharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease
The Lin28/let-7 axis regulates metabolic pathways in normal and pathological contexts. Here the authors show that pharmacological inhibition of Lin28 protects against lipid accumulation in multiple preclinical models of nonalcoholic fatty liver disease.
- Evangelia Lekka
- , Aleksandra Kokanovic
- & Jonathan Hall
-
Article
| Open AccessIntracellular phase separation of globular proteins facilitated by short cationic peptides
Phase separation provides intracellular organisation via membraneless entities called biomolecular condensates. Here, the authors show that short, cationic peptide tags can drive biomolecular condensation of engineered proteins in E. coli through associative interactions with RNA.
- Vivian Yeong
- , Jou-wen Wang
- & Allie C. Obermeyer
-
Article
| Open AccessBiomolecular condensate phase diagrams with a combinatorial microdroplet platform
A central concept for characterising phase-separating systems is the phase diagram but generation of such diagrams for biomolecular systems is typically slow and low-throughput. Here the authors describe PhaseScan, a combinatorial droplet microfluidic platform for high-resolution acquisition of multidimensional biomolecular phase diagrams.
- William E. Arter
- , Runzhang Qi
- & Tuomas P. J. Knowles
-
Article
| Open AccessRational enzyme design for enabling biocatalytic Baldwin cyclization and asymmetric synthesis of chiral heterocycles
Chiral heterocyclic compounds are privileged structures in medicinal chemistry. Here, the authors report an in silico strategy for the enzymatic synthesis of pharmaceutically significant chiral N- and O-heterocycles via Baldwin cyclization of hydroxy- and amino-substituted epoxides and oxetanes using epoxide hydrolase mutants.
- Jun-Kuan Li
- , Ge Qu
- & Zhoutong Sun
-
Article
| Open AccessChemical reaction-mediated covalent localization of bacteria
Transplantation of helpful bacteria has been used to treat disease through modulating host microbiota. Here, the authors report a strategy to control bacteria localization in the jejunum, via an in vivo in-situ thiol-disulfide exchange reaction between surface-reactive bacteria and mucous.
- Huilong Luo
- , Yanmei Chen
- & Jinyao Liu
-
Article
| Open AccessBiosynthesis of mushroom-derived type II ganoderic acids by engineered yeast
The biosynthetic pathway of type II ganoderic acids (GAs) in Ganoderma lucidum, a traditional medicinal mushroom, is unknown. Here, the authors assemble the genome of type II GAs accumulating accession, identify CYPs involving in type II GAs biosynthesis, and achieve their production in engineered baker’s yeast.
- Wei Yuan
- , Chenjian Jiang
- & Han Xiao
-
Article
| Open AccessBackbone amides are determinants of Cl− selectivity in CLC ion channels
CLC-type channels selectively transport Cl− across biological membranes, but it is unclear how discrimination between anions is maintained. Here, authors use a combination of non-natural amino acid substitutions, electrophysiology, and molecular dynamics simulations to determine Cl− specificity within this family of ion channels.
- Lilia Leisle
- , Kin Lam
- & Alessio Accardi
-
Article
| Open AccessA growth selection system for the directed evolution of amine-forming or converting enzymes
Fast screening of enzymes is key for directed evolution of industrial biocatalysts. Here, the authors report a simple, high-throughput, and low-equipment-dependent growth selection system for engineering three enzymes for synthesis of chiral amines.
- Shuke Wu
- , Chao Xiang
- & Uwe T. Bornscheuer
-
Article
| Open AccessNon-classical ferroptosis inhibition by a small molecule targeting PHB2
Ferroptosis is a promising therapeutic target for a variety of diseases, but a majority of known ferroptosis inhibitors belong to either antioxidants or iron chelators. Here, the authors discover a new non-classical small molecule inhibitor that is a PHB2 binder and show it ameliorates liver damage in an acute liver injury model.
- Wei Yang
- , Bo Mu
- & Shengyong Yang
-
Article
| Open AccessTotal enzymatic synthesis of cis-α-irone from a simple carbon source
Retrosynthetic pathway design using promiscuous enzymes can provide a solution to the biosynthetic production of natural products. Here, the authors design a pathway for the production of cis-α-irone with a promiscuous methyltransferase using structure-guided enzyme engineering strategies.
- Xixian Chen
- , Rehka T
- & Isabelle André
-
Article
| Open AccessChemoenzymatic synthesis of sulfur-linked sugar polymers as heparanase inhibitors
Heparin is a family of complex carbohydrates binding to proteins to modulate cell activities. Here the authors report the synthesis, and conformations simulations of S-linked hemi-A heparosan [GlcA-S-GlcNAc]n, a thio-glycosidic uncleavable polysaccharide, and test it as human heparanase inhibitor.
- Peng He
- , Xing Zhang
- & Paul L. DeAngelis
-
Article
| Open AccessShedding light on the base-pair opening dynamics of nucleic acids in living human cells
Base-pair opening is important for nucleic acids to exert biological functions, but studying its dynamics inside living cells is challenging. Here, the authors determine the base-pair opening kinetics of hairpin and G-quadruplex structures inside living human cells by the in-cell NMR technique, and demonstrate a difference in dynamics of nucleic acids between in-cell and in vitro conditions.
- Yudai Yamaoki
- , Takashi Nagata
- & Masato Katahira
-
Article
| Open AccessThiocarbazate building blocks enable the construction of azapeptides for rapid development of therapeutic candidates
The rapid protease degradation of peptides is currently limiting their therapeutic utility. Here, the authors report functionalised thiocarbazate scaffolds as precursors of aza-amino acids that can be integrated in peptide sequences, extending their bioavailability, and demonstrate this on FSSE/P5779 and bradykinin.
- Ahmad Altiti
- , Mingzhu He
- & Yousef Al-Abed
-
Article
| Open AccessOrthogonal glycolytic pathway enables directed evolution of noncanonical cofactor oxidase
Engineering enzymes to accept noncanonical cofactor biomimetics is difficult. Here, the authors establish a self-sufficient growth selection method and demonstrate its application in engineering the Lactobacillus pentosus NADH oxidase to efficiently recycle reduced nicotinamide mononucleotide (NMNH).
- Edward King
- , Sarah Maxel
- & Han Li
-
Article
| Open AccessInsights into protein post-translational modification landscapes of individual human cells by trapped ion mobility time-of-flight mass spectrometry
Single-cell proteomics is an emerging approach to study cellular heterogeneity but its coverage is still limited. Here, the authors develop a single-cell proteomics approach with improved protein sequence coverage, allowing them to quantify PTMs and characterize effects of inhibitor treatment in single human cells.
- Benjamin C. Orsburn
- , Yuting Yuan
- & Namandjé N. Bumpus
-
Article
| Open AccessStructure- and computational-aided engineering of an oxidase to produce isoeugenol from a lignin-derived compound
Lignin can be depolymerized into 4-alkylphenols by chemical means. Here the authors show a three-step computational-assisted enzyme engineering process to generate a biocatalyst for the conversion of lignin-derived 4-n-propylguaiacol into isoeugenol, a valuable compound.
- Yiming Guo
- , Laura Alvigini
- & Marco W. Fraaije
-
Article
| Open AccessConstruction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein–protein interaction inhibitor
Chemical libraries with skeleton diversity are important for drug discovery. Here, the authors establish a synthetic methodology-based compound library (SMBL), and apply it to identify a small-molecule inhibitor to interrupt a challenging target: the protein–protein interaction (PPI) of GIT1/β-Pix.
- Jing Gu
- , Rui-Kun Peng
- & Qin Ouyang
-
Article
| Open AccessBiodegradation of highly crystallized poly(ethylene terephthalate) through cell surface codisplay of bacterial PETase and hydrophobin
High-crystallinity poly(ethylene terephthalate) is a major recycling challenge. Here, the authors show an engineered whole-cell biocatalyst showing adhesive hydrophobin and PETase on the surface of cells, for biodegradation of PET.
- Zhuozhi Chen
- , Rongdi Duan
- & Zefang Wang
-
Article
| Open AccessStructural basis of synthetic agonist activation of the nuclear receptor REV-ERB
The nuclear receptor REV-ERBα is a receptor for heme and plays a role in a range of physiological processes. Here, the authors provide the first structure of REV-ERB bound to a synthetic nonporphyrin ligand defining key mechanistic differences to how heme binds.
- Meghan H. Murray
- , Aurore Cecile Valfort
- & Thomas P. Burris
-
Article
| Open AccessHow Carvedilol activates β2-adrenoceptors
How carvedilol, a β1-blocker, activates β2-adrenoceptors, is unclear. Here, the authors resolve this enigma and show that carvedilol drives all of its detectable cellular β2-adrenoceptor signals by slow and low efficacy G protein activation.
- Tobias Benkel
- , Mirjam Zimmermann
- & Evi Kostenis
-
Article
| Open AccessDNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance
DNA is well-documented to stimulate immune response. Here the authors show that the activation of cyclic GMP-AMP synthase (cGAS) depends on DNA mechanical flexibility, itself determined by DNA-sequence, damage and length.
- Lina Wang
- , Siru Li
- & Qingkai Yang
-
Article
| Open AccessA glutamine-based single α-helix scaffold to target globular proteins
Targeting biomedically relevant protein-protein interactions is a long-lasting challenge in medicinal chemistry. Here, the authors develop a single α-helical peptide scaffold that can be tailored to target globular proteins of biomedical interest.
- Albert Escobedo
- , Jonathan Piccirillo
- & Xavier Salvatella
-
Article
| Open AccessXNAzymes targeting the SARS-CoV-2 genome inhibit viral infection
RNA viruses have been responsible for large-scale epidemics and pandemics throughout the last few centuries. Here, the authors show the design, synthesis and screening of artificial RNA endonuclease XNAzymes capable of cleaving genomic SARS-CoV-2 RNA and self-assembling into enzymatic nanostructures inhibiting cellular viral replication.
- Pehuén Pereyra Gerber
- , Maria J. Donde
- & Alexander I. Taylor
-
Article
| Open AccessMultiplexed and reproducible high content screening of live and fixed cells using Dye Drop
It is currently difficult to perform accurate single-cell assays in 384-well plates. Here the authors report Dye Drop which uses sequential density displacement and microscopy for multi-step assays on cells, and use this to collect single-cell dose-response data for small molecules in breast cancer cells.
- Caitlin E. Mills
- , Kartik Subramanian
- & Peter K. Sorger
-
Article
| Open AccessAnti-infective therapy using species-specific activators of Staphylococcus aureus ClpP
The development of selective ClpP activators targeting only the MRSA isolates without interfering with the human variant is currently challenging. Here, the authors report on the structure-based design of enantiomers of ZG197 and identify the discriminator factor between the proteins.
- Bingyan Wei
- , Tao Zhang
- & Cai-Guang Yang
-
Article
| Open AccessA fluorogenic probe for predicting treatment response in non-small cell lung cancer with EGFR-activating mutations
The presence of activating epidermal growth factor receptor (EGFR) mutations in patients with lung cancer correlates to improved response to EGFR-tyrosine kinase inhibitors. Here, the authors present a fluorescence-activated cell sorting assay to identify EGFR mutations with functional activity in patients and demonstrate its utility in predicting response to EGFR-TKI.
- Hui Deng
- , Qian Lei
- & Weimin Li
-
Article
| Open AccessSite-selective photocatalytic functionalization of peptides and proteins at selenocysteine
The modification of peptides and proteins for application in drug discovery and chemical biology is currently a rapidly growing field of research. Here, the authors report a photocatalytic diselenide contraction method for the dimerization and site-specific functionalisation of peptides and protein.
- Luke J. Dowman
- , Sameer S. Kulkarni
- & Richard J. Payne
-
Article
| Open AccessDesign and directed evolution of noncanonical β-stereoselective metalloglycosidases
Metallohydrolases are ubiquitous enzymes. Here the authors show the design and biochemical characterisation of metalloglycosidase by constructing a hydrolytically active Zn-binding site within a barrel-shaped outer membrane protein OmpF.
- Woo Jae Jeong
- & Woon Ju Song
-
Article
| Open AccessGlycolytic flux control by drugging phosphoglycolate phosphatase
Targeting cellular glucose metabolism is a therapeutic strategy in human diseases such as autoimmunity or cancer. Here, the authors demonstrate the druggability of phosphoglycolate phosphatase, and validate an alternative approach to control glycolysis.
- Elisabeth Jeanclos
- , Jan Schlötzer
- & Antje Gohla
-
Article
| Open AccessCK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site
Here the authors identify SUZ12 as a cellular substate of casein kinase 2 (CK2), and show this phosphorylation changes the active site structure of Polycomb repressive complex 2 (PRC2) and promotes PRC2 function in cell identity maintenance during stem cell differentiation.
- Lihu Gong
- , Xiuli Liu
- & Xin Liu
-
Article
| Open AccessDiscovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice
Cryptochromes are transcriptional regulators of the circadian clock in mammals, and genetic loss of cryptochromes reduces p53-associated cancer risk in mice. Here the authors report the discovery of small molecule M47, which destabilizes cryptochrome 1 and extends the lifespan of p53 knock-out mice.
- Seref Gul
- , Yasemin Kubra Akyel
- & Ibrahim Halil Kavakli
-
Article
| Open AccessPharmacological blockade of TEAD–YAP reveals its therapeutic limitation in cancer cells
Previously, the small molecule inhibitor of transcriptional enhanced associate domain (TEAD) MGH-CP1 has been described in stem cells. Here, the authors demonstrate the utility of MGH-CP1 in cancer therapy and find treatment to increase Akt pathway activation via TEAD-Vgll3 activation, presenting a rationale for combination with Akt inhibition.
- Yang Sun
- , Lu Hu
- & Xu Wu
-
Article
| Open AccessA biomimetic electrostatic assistance for guiding and promoting N-terminal protein chemical modification
Phosphorylation is a mechanism used by cells to promote proteins-biomolecules association. Here, the authors show the effect of the interactions between proteins equipped with positively charged arginines and peptides harbouring negatively charged phosphoserines, enabling rate acceleration and chemical processes in dilute conditions.
- Nathalie Ollivier
- , Magalie Sénéchal
- & Oleg Melnyk
-
Article
| Open AccessSolar-driven methanogenesis with ultrahigh selectivity by turning down H2 production at biotic-abiotic interface
While the combination of synthetic and biological systems offers an appealing strategy for solar-to-fuel conversion, such hybrid systems typically suffer from low selectivity. Here, authors integrate a bimetallic alloy with a CdS-containing methanogen for selective CO2 reduction to methane.
- Jie Ye
- , Chao Wang
- & Yujie Xiong
-
Article
| Open AccessEndowing homodimeric carbamoyltransferase GdmN with iterative functions through structural characterization and mechanistic studies
Carbamoyltransferases are a class of enzymes catalyzing carbamoylation of primary and secondary metabolites. Here, the authors show the molecular structure of the ansamycin-modifying carbamoyltransferase GdmN and repurpose the enzyme for the iterative carbamoylation of ansamitocins.
- Jianhua Wei
- , Xuan Zhang
- & Linquan Bai
-
Article
| Open AccessHIF1α-AS1 is a DNA:DNA:RNA triplex-forming lncRNA interacting with the HUSH complex
Using a composite bioinformatics approach, the DNA:DNA:RNA triplex-forming lncRNAs HIF1α-AS1 was identified in human endothelial cells which recruits an epigenetic silencing complex to limit expression of triplex target genes.
- Matthias S. Leisegang
- , Jasleen Kaur Bains
- & Ralf P. Brandes
-
Article
| Open AccessUnexpected assembly machinery for 4(3H)-quinazolinone scaffold synthesis
4(3H)-quinazolinone is the core scaffold in more than 200 natural alkaloids and numerous drugs. Here, the authors show an alternative assembly machinery for 4(3H)-quinazolinone mainly includes a two-module NRPS catalysing tripeptide formation, unusual N-3 original sources and an α-KGD catalysing the C-N bond oxidative cleavage of a tripeptide to form a dipeptide.
- Xi-Wei Chen
- , Li Rao
- & Yi Zou
-
Article
| Open AccessThe occurrence of ansamers in the synthesis of cyclic peptides
The occurrence of isomers of the bicyclic octapeptide α-amanitin, which presents a macrolactam with a tryptathionine cross-link forming a handle, has been reported under the term of atropoisomers. Here, the authors synthesize its analogs and analyse their isomers, proposing and describing for them the term ansamer.
- Guiyang Yao
- , Simone Kosol
- & Roderich D. Süssmuth
-
Article
| Open AccessMicrofluidic space coding for multiplexed nucleic acid detection via CRISPR-Cas12a and recombinase polymerase amplification
Fast, low-cost and multiplexed nucleic acid detection is challenging. Here the authors report a strategy that couples microfluidic space coding, CRISPRCas12a, and multiplex RPA for the rapid detection of up to 30 targets with only one fluorescent probe.
- Zhichen Xu
- , Dongjuan Chen
- & Maili Liu
-
Article
| Open AccessOxygen mediated oxidative couplings of flavones in alkaline water
Catalysed oxidative C-C bond formation reactions are important in the synthesis of natural products, but poorly tolerated by polyphenolic flavones. Here the authors report the reactivity of molecular oxygen in alkaline water without added catalyst for the synthesis of a collection of flavone dimers and trimers.
- Xin Yang
- , Sophie Hui Min Lim
- & Dejian Huang
Browse broader subjects
Browse narrower subjects
- Biocatalysis
- Biophysical chemistry
- Biosynthesis
- Carbohydrates
- Chemical ecology
- Chemical genetics
- Chemical libraries
- Chemical modification
- Chemical tools
- Cheminformatics
- Combinatorial libraries
- Computational chemistry
- DNA
- Drug delivery
- Enzyme mechanisms
- Enzymes
- Glycobiology
- Glycomics
- Ion channels
- Kinases
- Lipidomics
- Lipids
- Mechanism of action
- Membranes
- Metabolic pathways
- Metabolomics
- Metals
- Natural products
- Networks and systems biology
- Nucleic acids
- Peptides
- Pharmacology
- Post-translational modifications
- Proteases
- Protein design
- Protein folding
- Proteins
- Proteomics
- RNA
- Screening
- Small molecules
- Synthetic biology
- Target identification
- Target validation
- Transporters