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| Open AccessHighly-sensitive label-free deep profiling of N-glycans released from biomedically-relevant samples
Glycans can serve as disease biomarkers. Here, the authors use label-free capillary electrophoresis-mass spectrometry for N-glycan profiling of minute sample amounts, resolving and characterizing previously undetected highly sialylated glycans and linkage isomers in a single analysis.
- Anne-Lise Marie
- , Somak Ray
- & Alexander R. Ivanov
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Article
| Open AccessModulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO
The two-component regulatory system VraRS regulates transcription of penicillin-binding protein 2 in response to cell wall antimicrobials. Here, Lu et al. show that an enzyme from the wall teichoic acid biosynthetic pathway of MRSA can also modulate the expression of virulence factors such as Staphylococcal protein A via VraRS.
- Yunfu Lu
- , Feifei Chen
- & Lefu Lan
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Article
| Open AccessDigital nanoreactors to control absolute stoichiometry and spatiotemporal behavior of DNA receptors within lipid bilayers
Resolving the stoichiometry of membrane protein interactions is challenging but is vital to understand cell signalling. Using lipid-bound DNA receptors as a model for membrane proteins, the authors present a platform to achieve stoichiometric, spatial and temporal control over their interactions.
- Vishal Maingi
- , Zhao Zhang
- & Paul W. K. Rothemund
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Article
| Open AccessAmide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides
Naturally occurring peptides with high membrane permeability often have backbone ester bonds. Here, the authors investigated the effect of an amide-to-ester substitution on membrane permeability of peptides and found the substitution is useful for improving membrane permeability of cyclic peptides.
- Yuki Hosono
- , Satoshi Uchida
- & Shinsuke Sando
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Article
| Open AccessInsights into membrane association of the SMP domain of extended synaptotagmin
The SMP domain of E-Syts is a newly identified lipid transfer module with unclear mechanisms. Here, authors show that it uses its tip region to associate with the extremely curved or negatively charged membranes to extract and unload lipids.
- Yunyun Wang
- , Zhenni Li
- & Xin Bian
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Article
| Open AccessRibozyme-mediated RNA synthesis and replication in a model Hadean microenvironment
Non-equilibrium conditions at heated water-air interfaces can model Hadean microenvironments. Here, the authors show that such conditions enable one-pot synthesis, strand release and folding of functional RNAs similar to modern biological systems.
- Annalena Salditt
- , Leonie Karr
- & Hannes Mutschler
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Article
| Open AccessPrecise programming of multigene expression stoichiometry in mammalian cells by a modular and programmable transcriptional system
Context-dependency of mammalian transcriptional elements has hindered the quantitative investigation of multigene expression stoichiometry and its biological functions. Here the authors present a host-orthogonal transcriptional system that drives tunable gene expression in mammalian cells, enabling predictive fine-tuning of multi-gene expression stoichiometry and the production optimization of virus-like particles from mammalian cells.
- Chenrui Qin
- , Yanhui Xiang
- & Chunbo Lou
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Article
| Open AccessTrio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
Dual-pharmacophore DNA-Encoded Libraries (DELs) can generate large libraries, but linker optimisation is challenging. Here, the authors report a trio-pharmacophore DEL (T-DEL) for both de novo fragment identification and linker optimization of known fragment pairs.
- Meiying Cui
- , Dzung Nguyen
- & Yixin Zhang
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Article
| Open AccessStructural basis of selective cannabinoid CB2 receptor activation
Cannabinoid CB2 receptor (CB2R) agonists are investigated as therapeutic agents in the clinic. Here, authors report the discovery of LEI-102, a CB2R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate selective CB2R activation.
- Xiaoting Li
- , Hao Chang
- & Tian Hua
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Article
| Open AccessReference compounds for characterizing cellular injury in high-content cellular morphology assays
Cellular nuisance compounds are a burden in chemical biology and drug screening. Here the authors profile prototypical cytotoxic and nuisance compounds using the cell painting assay to systematically characterise cellular morphologies associated with compound-dependent cellular injury and nuisance activity.
- Jayme L. Dahlin
- , Bruce K. Hua
- & Bridget K. Wagner
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Article
| Open AccessAutocatalytic base editing for RNA-responsive translational control
Genetic circuits that control transgene expression in response to pre-defined transcriptional cues would enable the development of smart therapeutics. Here the authors engineer programmable RNA sensors, DART VADARs, in which ADARs autocatalytically convert target hybridization into a translational output, thus amplifying editing by endogenous ADAR via positive feedback and conferring high dynamic range and a small genetic footprint.
- Raphaël V. Gayet
- , Katherine Ilia
- & James J. Collins
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Article
| Open AccessDecrypting the programming of β-methylation in virginiamycin M biosynthesis
Biosynthesis of complex polyketides by polyketide synthases often relies on trans-acting enzymes to modify the intermediates. Here, the authors elucidate how β-methylation enzymes identify their substrates. The recognition is imperfect, resulting in a doubly β-methylated virginiamycin derivative.
- Sabrina Collin
- , Russell J. Cox
- & Arnaud Gruez
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Article
| Open AccessA general highly efficient synthesis of biocompatible rhodamine dyes and probes for live-cell multicolor nanoscopy
Rhodamines are privileged fluorescent dyes for labelling intracellular structures in living cells. Here, the authors present a facile protecting-group-free synthesis permitting generation of a wide range of symmetrical and unsymmetrical 4-carboxyrhodamines covering the whole visible spectrum.
- Jonas Bucevičius
- , Rūta Gerasimaitė
- & Gražvydas Lukinavičius
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Article
| Open AccessOptical control of PIEZO1 channels
PIEZO proteins are large, mechanically-activated trimeric ion channels. Here the authors report a light-gated mouse PIEZO1 channel, mOP1, whereby an azobenzene-based photoswitch covalently localised at the extracellular apex of a transmembrane helix, rapidly triggers channel gating on light irradiation.
- Francisco Andrés Peralta
- , Mélaine Balcon
- & Thomas Grutter
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Article
| Open AccessStructural basis of HIV-1 maturation inhibitor binding and activity
HIV maturation inhibitors such as bevirimat (BVM) interfering with Gag processing are emerging as alternative anti-retroviral drug candidates. Here, the authors report structures of assemblies of HIV-1 Gag fragments spanning the CA C-terminal domain and SP1 region bound to BVM.
- Sucharita Sarkar
- , Kaneil K. Zadrozny
- & Tatyana Polenova
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Article
| Open AccessA covalent BTK ternary complex compatible with targeted protein degradation
Bridging covalent ligand discovery with chimeric degrader design has emerged as a mechanism to target proteins that lack enzymatic activity or are intractable. Here, the authors use biochemical and cellular tools to deconvolute the role of covalent modification in targeted protein degradation using Bruton’s tyrosine kinase.
- James Schiemer
- , Andrew Maxwell
- & Matthew F. Calabrese
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Article
| Open AccessStructural consequences of turnover-induced homocitrate loss in nitrogenase
Biological nitrogen fixation is achieved by nitrogenase, but the mechanism remains enigmatic. Here, the authors report high resolution single particle cryoEM structures of homocitrate-compromised MoFe-proteins and unveil a new binding partner.
- Rebeccah A. Warmack
- , Ailiena O. Maggiolo
- & Douglas C. Rees
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Article
| Open AccessNoncanonical amino acids as doubly bio-orthogonal handles for one-pot preparation of protein multiconjugates
Site-specific protein multi-conjugates are important for both scientific and translational research. Here, the authors genetically encode unnatural amino acids which contain both tetrazine and azide, and use the doubly bio-orthogonal handles to generate bi- and tri-conjugate proteins in high yields.
- Yong Wang
- , Jingming Zhang
- & Tao Liu
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Article
| Open AccessIdentification of global inhibitors of cellular glycosylation
Here, the authors discover small molecules that inhibit glycosylation processes that occur in the Golgi apparatus of cells. The molecules reversibly inhibit formation of elaborate glycan structures without affecting secretion of glycoproteins.
- Daniel Madriz Sørensen
- , Christian Büll
- & Yoshiki Narimatsu
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Article
| Open AccessNicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity
Nicotine, a metabolite of the NAD+ metabolic pathway, has been found to possess anti-inflammatory and neuroprotective properties, yet the underlying molecular mechanisms remained unknown. Here, the authors show that low-dose nicotine promotes SIRT1 deacetylation of NAMPT and enhanced NAMPT activity which boosts NAD generation and improves age related symptoms.
- Liang Yang
- , Junfeng Shen
- & Xiang Li
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Article
| Open AccessWatching the release of a photopharmacological drug from tubulin using time-resolved serial crystallography
Photopharmacology manipulates the biological activity of small molecules by light. Using an X-ray laser, the authors follow the release of the drug azo-combretastatin A4 from tubulin and the concomitant structural changes over nine orders of magnitude in time.
- Maximilian Wranik
- , Tobias Weinert
- & Jörg Standfuss
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Article
| Open AccessChemoproteomic discovery of a human RNA ligase
RNA ligases are present across all forms of life. Here, the hitherto uncharacterised human protein C12orf29 was identified as a human enzyme promoting RNA ligation between 5′-PO4 and 3′-OH termini. This data provides the groundwork for establishing a human RNA repair pathway.
- Yizhi Yuan
- , Florian M. Stumpf
- & Andreas Marx
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Article
| Open AccessA genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase
The authors develop a Vitamin K-dependent apoptotic reporter cell line for large-scale screening of enzymes associated with Vitamin K-dependent carboxylation and identify ferroptosis suppressor protein 1 (FSP1) as responsible for warfarin-resistant vitamin K reduction.
- Da-Yun Jin
- , Xuejie Chen
- & Jian-Ke Tie
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Article
| Open AccessControlled sequential in situ self-assembly and disassembly of a fluorogenic cisplatin prodrug for cancer theranostics
Manipulating molecular self-assembly and disassembly in vivo may permit temporal control of drug delivery and release. Here, the authors report a fluorogenic cisplatin prodrug for cancer theranostics by leveraging stimuli-triggered in situ self-assembly and intracellular disassembly processes.
- Xidan Wen
- , Rui Zhang
- & Deju Ye
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Article
| Open AccessAccelerating inhibitor discovery for deubiquitinating enzymes
Deubiquitinases (DUBs) are key signaling enzymes, many of which lack selective inhibitors. Chan et al. pair a DUB-focused covalent library to mass spectrometry activity-based protein profiling, leading to selective hits against 23 endogenous DUBs and a first-in-class VCPIP1 probe with nanomolar potency.
- Wai Cheung Chan
- , Xiaoxi Liu
- & Sara J. Buhrlage
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Article
| Open AccessDiverse secondary metabolites are expressed in particle-associated and free-living microorganisms of the permanently anoxic Cariaco Basin
Genome mining for biosynthetic gene clusters (BGCs) can be used for the discovery of new compounds of biotechnological interest. Here, the authors use metagenomics and metatranscriptomics to identify diverse BGCs in free-living and particle-associated microbial communities through the stratified water column of the Cariaco Basin, Venezuela.
- David Geller-McGrath
- , Paraskevi Mara
- & Maria Pachiadaki
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Article
| Open AccessInsights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition
Intermodular recognition in polyketide synthase (PKS) is a key prerequisite for catalysis and assembly-line engineering. Here, the authors present a specific domain interaction between modules and an evolution-oriented strategy for PKS engineering derived from the enoylreduction module of azalomycin F.
- Guifa Zhai
- , Yan Zhu
- & Yuhui Sun
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Article
| Open AccessPivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis
Here the authors demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by nitric oxide (NO). They also isolate a unique modulator (DBIC) that inhibits S-nitrosylation of DNMT3B, which mitigates cell proliferation and tumorigenic conversion in vivo.
- Kosaku Okuda
- , Kengo Nakahara
- & Takashi Uehara
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Article
| Open AccessLipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response
Circulating lipids can influence immune cell function, which could have implications for inflammatory diseases such as rheumatoid arthritis. Here, the authors use Mendelian randomization to identify genes whose expression is influenced by triglyceride levels in blood, implicating genes involved in lipid metabolism and allergic response.
- Koen F. Dekkers
- , Roderick C. Slieker
- & Bastiaan T. Heijmans
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Article
| Open AccessA split ribozyme that links detection of a native RNA to orthogonal protein outputs
RNA provides a unique readout of a cell’s identity, physiologic status, and phenotype. Here the authors deliver an RNA sensing system that can use the information contained within cellular RNA to selectively control the activity of genetic programs.
- Lauren Gambill
- , August Staubus
- & James Chappell
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Article
| Open AccessHost-microbe co-metabolism via MCAD generates circulating metabolites including hippuric acid
Here, using a mouse model, the authors report a previously undescribed role for medium-chain acyl-CoA dehydrogenase in host metabolism of gut microbiota metabolites, and show that circulating compounds, including the abundant organic acid hippurate, depend on host-microbe co-metabolism of phenylalanine by Clostridium sporogenes.
- Kali M. Pruss
- , Haoqing Chen
- & Dylan Dodd
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Article
| Open AccessDesign and characterization of a protein fold switching network
In this work the authors investigate the structure-sequence dependance. The ability to design and characterize proteins at interfaces between three common folds suggests that fold switching is an intrinsic feature of protein folding language and likely important in the evolution of protein structure and function.
- Biao Ruan
- , Yanan He
- & Philip N. Bryan
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Article
| Open AccessBiomolecular condensates formed by designer minimalistic peptides
The molecular mechanisms underlying the formation of biomolecular condensates have not been fully elucidated. Here the authors show that the LLPS propensity, dynamics, and encapsulation efficiency of designed peptide condensates can be tuned by subtle changes to the peptide composition.
- Avigail Baruch Leshem
- , Sian Sloan-Dennison
- & Ayala Lampel
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Article
| Open AccessA FRET-based respirasome assembly screen identifies spleen tyrosine kinase as a target to improve muscle mitochondrial respiration and exercise performance in mice
Mitochondrial supercomplex assembly may efficiently supply energy, yet its role remains controversial. Here, the authors show that SYK inhibitors increase supercomplex assembly and mitochondrial respiration in cells and can enhance exercise performance in mice.
- Ami Kobayashi
- , Kotaro Azuma
- & Satoshi Inoue
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Article
| Open AccessA natural biological adhesive from snail mucus for wound repair
Natural adhesives have received a lot of attention recently. Here, the authors develop a natural biological adhesive from snail mucus that can adhere to wet tissue and be used to accelerate healing of skin wounds.
- Tuo Deng
- , Dongxiu Gao
- & Mingyi Wu
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Article
| Open AccessDifferential sensing with arrays of de novo designed peptide assemblies
Differential sensing aims to mimic senses such as taste and smell through the use of synthetic receptors. Here, the authors show that arrays of de novo designed peptide assemblies can be used as sensor components to distinguish various analytes and complex mixtures.
- William M. Dawson
- , Kathryn L. Shelley
- & Derek N. Woolfson
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Article
| Open AccessStructural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins
Asymmetric reduction of prochiral ketones is challenging. Here, the authors identify and solve the structure of anthrol reductase CbAR, whose variant H162F can convert 1,3-cyclodiketones and α-haloacetophenones to the corresponding chiral alcohols.
- Xiaodong Hou
- , Huibin Xu
- & Yijian Rao
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Article
| Open AccessUncovering a miltiradiene biosynthetic gene cluster in the Lamiaceae reveals a dynamic evolutionary trajectory
A diterpenoid biosynthetic gene cluster (BGC) has been identified in a few species in the Lamiaceae (mint) family, but its origin and evolution remain unclear. Here, the authors report assembly of genomes of three species within the family and reveal the dynamic evolutionary trajectory of the BGC.
- Abigail E. Bryson
- , Emily R. Lanier
- & Björn Hamberger
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Article
| Open AccessEmission of floral volatiles is facilitated by cell-wall non-specific lipid transfer proteins
Volatile compounds to be released from the plant cell to the atmosphere must cross the cell wall. Here the authors show that cell-wall localized non-specific lipid transfer proteins facilitate the diffusion of volatiles across the hydrophilic cell wall.
- Pan Liao
- , Itay Maoz
- & Natalia Dudareva
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Article
| Open AccessAnnotation of natural product compound families using molecular networking topology and structural similarity fingerprinting
Comparing experimental mass spectra to reference spectra can enable natural product identification, but these spectral libraries are often incomplete and not universally applicable. Here, the authors present SNAP-MS, a tool that allows assigning compound families without experimental or calculated reference spectra.
- Nicholas J. Morehouse
- , Trevor N. Clark
- & Roger G. Linington
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Article
| Open AccessRevealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling
Visualizing endogenous GPCRs is challenging. Here the authors generate mice with an enzyme self-label genome-edited into the endogenous glucagon-like peptide-1 receptor locus, design fluorescent dyes for specific labelling in complex tissue, and reveal tissue-level organisation and dynamics of an endogenous class B GPCR.
- Julia Ast
- , Daniela Nasteska
- & David J. Hodson
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Article
| Open AccessEnhancement of a prime editing system via optimal recruitment of the pioneer transcription factor P65
Prime editing represents a great advance to the genome editing field but is currently limited by the editing efficiency. Here the authors look to improve the efficiency by recruiting target proteins and show that the transcription factor P65 could enhance the desired editing outcomes at different gene loci.
- Ronghao Chen
- , Yu Cao
- & Xueli Zhang
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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
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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
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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
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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
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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
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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
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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
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