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Article
| Open AccessHost heparan sulfate promotes ACE2 super-cluster assembly and enhances SARS-CoV-2-associated syncytium formation
The molecular mechanism of syncytium formation during SARS-CoV-2 infection is not fully understood. Zhang et al. now show that cell surface heparan sulfate enhances spike-induced ACE2 clustering and cell-cell fusion, which depends on a conserved ACE2 linker and is blocked by a heparan sulfate binding drug.
- Qi Zhang
- , Weichun Tang
- & Yihong Ye
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Article
| Open AccessN-terminal α-amino SUMOylation of cofilin-1 is critical for its regulation of actin depolymerization
SUMOylation plays a key role in modulating protein function. Here, the authors uncover a form of SUMOylation, termed N-αSUMOylation, where SUMO1 attaches to the N-terminus of cofilin1. This SUMOylation promotes cofilin-1 binding to F-actin and cofilin-induced actin depolymerization.
- Weiji Weng
- , Xiaokun Gu
- & Yong Li
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Article
| Open AccessGenetically encoded discovery of perfluoroaryl macrocycles that bind to albumin and exhibit extended circulation in vivo
Peptide-based therapeutics are promising therapeutic modalities, however, their prevalent drawback is poor circulation half-life in vivo. Here, the authors report the selection of albumin-binding macrocyclic peptides from genetically encoded libraries of peptides modified by perfluoroaryl-cysteine chemistry, with decafluoro-diphenylsulfone.
- Jeffrey Y. K. Wong
- , Arunika I. Ekanayake
- & Ratmir Derda
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Article
| Open AccessMembrane manipulation by free fatty acids improves microbial plant polyphenol synthesis
The inherent toxicity of the aromatic compounds to the chassis strain hampers further improvement of bioproduction. Here, the authors show that membrane rigidifying effect of resveratrol can be attenuated by exogenous supplementation of palmitelaidic acid or linoleic acid in fermentation of Corynebacterium glutamicum.
- Apilaasha Tharmasothirajan
- , Josef Melcr
- & Jan Marienhagen
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Article
| Open AccessMultidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization
The effects of E45A or P38A capsid mutations on HIV core stability and infectivity are reversed by R132T or T216I. Here, authors used structural and biophysical methods to reveal short- and long-range rearrangements that explain stability changes.
- Anna T. Gres
- , Karen A. Kirby
- & Stefan G. Sarafianos
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Article
| Open AccessChemical-induced phase transition and global conformational reorganization of chromatin
The authors show that adriamycin induces global changes on chromatin conformation associated with phase transitions mediated through Histone H1.
- Tengfei Wang
- , Shuxiang Shi
- & Chao-Po Lin
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Article
| Open AccessHeterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam
Here, the reaction of the suicide inhibitor sulbactam with the M. tuberculosis β-lactamase (BlaC) is investigated with time-resolved crystallography. Singular Value Decomposition is implemented to extract kinetic information despite changes in unit cell parameters during the time-course of the reaction.
- Tek Narsingh Malla
- , Kara Zielinski
- & Marius Schmidt
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Article
| Open AccessA cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses
Different types of lytic cell death can trigger an anti-tumor immune response. Here the authors report the design of a near infrared light controllable micron-scale oncolytic system, triggering lipid peroxidation and lytic cell death in tumors as well anti-tumor immunity in preclinical cancer models.
- Zhigui Zuo
- , Hao Yin
- & Qinyang Wang
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Article
| Open AccessTailored photoenzymatic systems for selective reduction of aliphatic and aromatic nitro compounds fueled by light
The selective enzymatic reduction of nitroaliphatic and nitroaromatic compounds is challenging. Here, the authors report selective (sun)light-driven photoenzymatic reduction of a wide variety of nitro compounds to aliphatic amines and amino-, azoxy- and azo-aromatics using flavin-dependent nitroreductases and chlorophyll as photocatalyst
- Alejandro Prats Luján
- , Mohammad Faizan Bhat
- & Gerrit J. Poelarends
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Article
| Open AccessO-methyltransferase-like enzyme catalyzed diazo installation in polyketide biosynthesis
Diazo compounds, such as kinamycin, are rare bioactive natural products whose assembly has been extensively studied, but the formation of the diazo group is elusive. Here, the authors report O-methyltransferase-like protein, AlpH, which is responsible for the l-glutamylhydrazine incorporation in kinamycin biosynthesis.
- Yuchun Zhao
- , Xiangyang Liu
- & Ming Jiang
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Article
| Open AccessDNA nanopores as artificial membrane channels for bioprotonics
Synthetic membrane channels have many potential applications, but interfacing membrane channels with electronic devices for efficient information transfer is challenging. Here the authors integrate membrane spanning DNA nanopores with bioprotonic contacts to create programmable, modular, and efficient artificial ion-channel interfaces.
- Le Luo
- , Swathi Manda
- & Marco Rolandi
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Article
| Open AccessSuppression of alpha-carbon racemization in peptide synthesis based on a thiol-labile amino protecting group
During solid-phase peptide synthesis (SPPS) inherent side reactions of the protected amino acids such as α-C racemization generate by-products that are hard to remove. Here, the authors report thiol-labile amino protecting group for SPPS, DNPBS group, which suppresses the main side reactions observed during conventional SPPS.
- Yifei Zhou
- , Hongjun Li
- & Chuanzheng Zhou
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Article
| Open AccessA portable regulatory RNA array design enables tunable and complex regulation across diverse bacteria
A lack of composable and tunable gene regulators has hindered efforts to engineer nonmodel bacteria and consortia. Here the authors deliver a tunable gene regulatory platform based on RNA arrays to control gene expression across different microbes.
- Baiyang Liu
- , Christian Cuba Samaniego
- & James Chappell
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Article
| Open AccessChemoenzymatic synthesis of genetically-encoded multivalent liquid N-glycan arrays
Cellular glycosylation is complex and heterogeneous, which is challenging to reproduce synthetically. Here, the authors report on enzymatic remodelling of multivalent glycosylated bacteriophages to produce genetically encoded library of N-glycans which can be used to measure glycan-protein interactions with lectins on the surface of live cells and organs.
- Chih-Lan Lin
- , Mirat Sojitra
- & Ratmir Derda
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Article
| Open AccessCircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications
Osteoarthritis is a prevalent age-related disease. Here, the authors show that that CircRREB1 is highly expressed in second generation chondrocytes and its deficiency can alleviate FASN related senescent phenotypes and osteoarthritis progression.
- Zhe Gong
- , Jinjin Zhu
- & Shuying Shen
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Article
| Open AccessVisualizing single-molecule conformational transition and binding dynamics of intrinsically disordered proteins
Intrinsically disordered proteins (IDPs) are highly dynamic and play pivotal roles in cellular processes but can be difficult to study. Here, the authors develop a single-molecule nanocircuit for the real-time monitoring of c-Myc conformational transitions and their interaction with ligands.
- Wenzhe Liu
- , Limin Chen
- & Xuefeng Guo
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Article
| Open AccessMetal-mediated DNA strand displacement and molecular device operations based on base-pair switching of 5-hydroxyuracil nucleobases
The development of dynamic DNA nanodevices, whose configuration and function are regulated by specific chemical inputs, represents a rapidly growing area in molecular science. Herein, the authors report the concept of metal-mediated base-pair switching to induce inter- and intramolecular DNA strand displacement in a metal-responsive manner.
- Yusuke Takezawa
- , Keita Mori
- & Mitsuhiko Shionoya
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Article
| Open AccessClick-electrochemistry for the rapid labeling of virus, bacteria and cell surfaces
Methods for direct covalent ligation of microorganism surfaces are scarce. Here, the authors developed a rapid electrochemical process for the direct covalent ligation and labelling of the surfaces of virus, bacteria and cells using N-methylluminol, a fully tyrosine-selective protein anchoring group.
- Sébastien Depienne
- , Mohammed Bouzelha
- & Sébastien G. Gouin
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Article
| Open AccessAn integrated proteome and transcriptome of B cell maturation defines poised activation states of transitional and mature B cells
B cells pursue specific genetic programs to facilitate downstream cellular functions. Here the authors identify, using a combination of proteomic, transcriptomic and functional analyses, a group of mRNAs related to early activation and antibody production that are expressed in B cells without corresponding proteins, hinting a ‘poised’ state of B cells.
- Fiamma Salerno
- , Andrew J. M. Howden
- & Martin Turner
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Comment
| Open AccessEpichaperomics reveals dysfunctional chaperone protein networks
Molecular chaperones establish essential protein-protein interaction networks. Modified versions of these assemblies are generally enriched in certain maladies. A study published in Nature Communications used epichaperomics to identify unique changes occurring in chaperone-formed protein networks during mitosis in cancer cells.
- Mark R. Woodford
- , Dimitra Bourboulia
- & Mehdi Mollapour
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Article
| Open AccessPyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming
Nitric oxide has been shown to target mitochondrial aconitase 2 and pyruvate dehydrogenase to reprogramme macrophage metabolism. Here, the authors extend these findings to show that lipoate is used to generate nitroxyl in this process.
- Erika M. Palmieri
- , Ronald Holewinski
- & Daniel W. McVicar
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Article
| Open AccessMetabolic glycan labeling immobilizes dendritic cell membrane and enhances antitumor efficacy of dendritic cell vaccine
Dendritic cell (DC) vaccines were among the first FDA-approved cancer immunotherapies but have been limited by the modest therapeutic efficacy. Here, authors report a facile metabolic glycan labeling approach to improving the cytotoxic T lymphocyte response and antitumor efficacy of DC vaccines.
- Joonsu Han
- , Rimsha Bhatta
- & Hua Wang
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Article
| Open AccessLenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation
Lenalidomide is effective for treating several hematological cancers but has teratogenic effect on the fetus. Here, the authors identify modifications that make lenalidomide more selective and effective when used as a stand-alone molecular glue or integrated in PROTACs.
- Satoshi Yamanaka
- , Hirotake Furihata
- & Tatsuya Sawasaki
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Article
| Open AccessExtensive breaking of genetic code degeneracy with non-canonical amino acids
Genetic code expansion is limited by the degeneracy of the 61 sense codons which encode for only 20 amino acids. Here, the authors show that by combining hyperaccurate ribosomes and in vitro transcribed tRNAs, dramatic and extensive breaking of sense codon degeneracy can be achieved.
- Clinton A. L. McFeely
- , Bipasana Shakya
- & Matthew C. T. Hartman
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Article
| Open AccessPharmacological perturbation of the phase-separating protein SMNDC1
SMNDC1 is a splicing factor that binds arginine methylation with its Tudor domain. Here, the authors study the protein’s phase-separating behavior and develop small-molecule Tudor domain inhibitors that perturb SMNDC1 function.
- Lennart Enders
- , Marton Siklos
- & Stefan Kubicek
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Article
| Open AccessQuantitative real-time in-cell imaging reveals heterogeneous clusters of proteins prior to condensation
The nucleation of biomolecular condensates is seldom quantified in living cells. Here, the authors show how protein clusters form before microscopically visible condensation and find a flat free-energy profile with active blocking of cluster growth.
- Chenyang Lan
- , Juhyeong Kim
- & Thorsten Hugel
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Article
| Open AccessBiosensor Guided Polyketide Synthases Engineering for Optimization of Domain Exchange Boundaries
Engineering polyketide synthases can be challenging due to the absence of efficient high-throughput methods. Here, the authors used a solubility biosensor to identify stable variants from libraries of modified polyketide synthases.
- Elias Englund
- , Matthias Schmidt
- & Jay D. Keasling
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Article
| Open AccessAuranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes
Decreased activity of the E1 ubiquitin-activating enzyme UBA1 can contribute to aging and diseases like Alzheimer’s and VEXAS syndrome. Here, the authors found that auranofin, a rheumatoid arthritis drug, can significantly boost UBA1 activity.
- Wenjing Yan
- , Yongwang Zhong
- & Shengyun Fang
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Article
| Open AccessCatalytic site flexibility facilitates the substrate and catalytic promiscuity of Vibrio dual lipase/transferase
Vibrio dual lipases/transferases are virulence-related enzymes, with both substrate and catalytic promiscuity. Wang et al reveal their prominent structural flexibility, proposing a catalytic site tuning mechanism underlying enzyme promiscuity.
- Chongyang Wang
- , Changshui Liu
- & Qingjun Ma
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Article
| Open AccessSmall molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels
Branched chain ketoacid dehydrogenase kinase (BDK) inhibits the activity of branched chain ketoacid dehydrogenase and branched chain amino acid degradation, implicated in several diseases. Here, the authors discover a BDK inhibitor and degrader that shows efficacy in rodent metabolism and heart failure models, as well as another class of BDK inhibitors that stabilizes BDK.
- Rachel J. Roth Flach
- , Eliza Bollinger
- & Kevin J. Filipski
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Article
| Open AccessMolecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome
Here the authors use fast kinetics, X-ray crystallography, and cryo-EM to uncover the mechanism of ribosome inhibition by amikacin and kanamycin. They find that amikacin binds near the P-site tRNA, offering new strategies to fight antibiotic resistance.
- Savannah M. Seely
- , Narayan P. Parajuli
- & Matthieu G. Gagnon
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Article
| Open AccessNitroalkanes as thioacyl equivalents to access thioamides and thiopeptides
Replacement of oxoamide units with thioamides in peptide therapeutics is a valuable tactic to improve biological activity and resistance to enzymatic hydrolysis. Here, the authors develop a direct coupling of readily available nitroalkane and amines with elemental sulfur and base and provide an efficient way to form thioamides and thiopeptides.
- Xiaonan Wang
- , Silong Xu
- & Jing Li
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Article
| Open AccessChemically programmed STING-activating nano-liposomal vesicles improve anticancer immunity
Agonists of the cytosolic DNA-sensing STING pathway potently remodel the tumour immune microenvironment to support anti-tumour adaptive immunity, but at the expense of adverse systemic inflammation. Here authors exchange the STING agonist MSA-2 with its prodrugs that are suitable for nano-liposomal delivery and thus achieve increased efficiency and decreased toxicity.
- Xiaona Chen
- , Fanchao Meng
- & Hangxiang Wang
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Article
| Open AccessPathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations
Signaling pathway selectivity downstream of GPCRs is not fully understood. Here, authors perform functional analysis of Frizzled mutants to uncover state-stabilizing residues or ‘micro-switches’ mediating selectivity towards Disheveled over G proteins.
- Lukas Grätz
- , Maria Kowalski-Jahn
- & Gunnar Schulte
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Article
| Open AccessSubunit gating resulting from individual protonation events in Kir2 channels
Here, authors introduced negative charges in the transmembrane helices in Kir2.2 channels generating pH-dependent sub-conductances. Molecular dynamics simulations show how protonation results in step-wise alterations of ion pooling and hence conductance, appearing as gated substates.
- Grigory Maksaev
- , Michael Bründl-Jirout
- & Colin G. Nichols
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Article
| Open AccessThe Gram-positive bacterium Romboutsia ilealis harbors a polysaccharide synthase that can produce (1,3;1,4)-β-d-glucans
(1,3;1,4)-β-d-Glucans are widely distributed in many organisms, but little is known about the enzymes responsible for their synthesis outside the grasses. Here, the authors report on the presence of (1,3;1,4)-β-d-glucans in the exopolysaccharides of the Gram-positive bacterium Romboutsia ilealis and identify and characterize the (1,3;1,4)-β-d-glucan synthase RiGT2.
- Shu-Chieh Chang
- , Mu-Rong Kao
- & Yves S. Y. Hsieh
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Article
| Open AccessA small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity
Here, the authors demonstrate that inhibition of PTP1B and PTPN2 in tumor cells and T-cells with a small molecule inhibitor represses the growth of immunogenic and cold tumors, and enhances response to anti-PD-1 immunotherapy without promoting immune-related toxicities.
- Shuwei Liang
- , Eric Tran
- & Tony Tiganis
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Article
| Open AccessDNA framework-engineered chimeras platform enables selectively targeted protein degradation
The lack of a universal platform for PROTAC development remains a major bottleneck. Here, the authors report modular DNA framework-based PROTACs (DbTACs) that enable precise control of the linker length and selective degradation of diverse targets in different cellular compartments using various warheads.
- Li Zhou
- , Bin Yu
- & Yi Ma
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Article
| Open AccessSupersulphides provide airway protection in viral and chronic lung diseases
The physiological roles of supersulphides and the enzymes that trigger their production in various airway diseases are not fully understood. Here, the authors show in animal models of viral and chronic lung diseases that supersulphide production can mitigate lung pathology and lethal effects, highlighting their protective role and potential as a therapeutic target.
- Tetsuro Matsunaga
- , Hirohito Sano
- & Takaaki Akaike
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Article
| Open AccessAn unconventional proanthocyanidin pathway in maize
Maize has an unconventional proanthocyanidin (PA) biosynthetic pathway which produces rare stereoisomers of PA monomers and dimers, highlighting an opportunity for further improving the nutritional value of maize.
- Nan Lu
- , Ji Hyung Jun
- & Richard A. Dixon
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Article
| Open AccessTargeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction
Dynamin-related protein 1 (Drp1) mediates physiological and pathological mitochondrial fission, and the latter can be selectively blocked by a peptide inhibitor. Here, the authors identify a small molecule that mimics the benefits of this peptide inhibitor in cells and a mouse model of endotoxemia.
- Luis Rios
- , Suman Pokhrel
- & Daria Mochly-Rosen
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Article
| Open AccessArchitecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair
B12-dependent human methylmalonly-CoA mutase (MMUT) requires the chaperone MMAA. The authors report the crystal structure of MMUT-MMAA, which shows a MMAA-driven conformational change in MMUT involved n B12 loading and repair and helps explain the effects of disease-causing MMAA-MMUT interface mutations.
- Romila Mascarenhas
- , Markus Ruetz
- & Ruma Banerjee
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Article
| Open AccessConformational restriction shapes the inhibition of a multidrug efflux adaptor protein
Multidrug efflux protein pumps are key players in bacterial antimicrobial resistance. Here, the authors show how dynamics of a periplasmic pump component can be targeted for efflux inhibition.
- Benjamin Russell Lewis
- , Muhammad R. Uddin
- & Eamonn Reading
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Article
| Open AccessEnabling programmable dynamic DNA chemistry using small-molecule DNA binders
The binding of small molecules to the double stranded DNA may significantly alter its stability and functionality, which is the basis for many therapeutic and sensing applications. Here, the authors report that DNA binders can be used to program reaction pathways of a dynamic DNA reaction, where DNA strand displacement can be tuned quantitatively according to the affinity, charge, and concentrations of a given DNA binder.
- Junpeng Xu
- , Guan Alex Wang
- & Feng Li
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Article
| Open AccessHypoRiPPAtlas as an Atlas of hypothetical natural products for mass spectrometry database search
A gap exists between large-scale genome mining and mass spectral datasets for natural product discovery. Here the authors bridge the gap by developing HypoRiPPAtlas, an Atlas of hypothetical natural product structures, which is ready-to-use for in silico database search of tandem mass spectra.
- Yi-Yuan Lee
- , Mustafa Guler
- & Hosein Mohimani
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Article
| Open AccessAffinity and cooperativity modulate ternary complex formation to drive targeted protein degradation
Targeted protein degradation using proteolysis targeting chimeras (PROTACs) represents an emergent therapeutic modality, however, the design of PROTACs is challenging due to multiple steps involved in PROTAC-induced degradation. Here, the authors establish a predictive framework to guide the design of potent degraders.
- Ryan P. Wurz
- , Huan Rui
- & Amit Vaish
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Article
| Open AccessHidden modes of DNA binding by human nuclear receptors
Nuclear receptors (NR) are drug-responsive master regulators. Here, authors map DNA binding profiles of all human NRs. Their MinSeq Find algorithm identifies masked NR binding sites in genomes and maps ~10% of orphan SNPs linked to numerous diseases.
- Devesh Bhimsaria
- , José A. Rodríguez-Martínez
- & Aseem Z. Ansari
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Article
| Open AccessCryo-EM structures of full-length integrin αIIbβ3 in native lipids
The structural basis of integrin signaling in health and disease is not fully understood. Here, the authors determine the cryoEM structure of full-length platelet integrin αIIbβ3 in its apo and eptifibatide-bound conformations in a native membrane environment.
- Brian D. Adair
- , Jian-Ping Xiong
- & M. Amin Arnaout
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Article
| Open AccessDeciphering intercellular signaling complexes by interaction-guided chemical proteomics
Systematic profiling of the indirect cell–cell interactions remains challenging. Here, the authors report a chemical proteomics method to identify ligand-receptor complexes formed between cell surface receptors and secreted proteins from neighboring cells.
- Jiangnan Zheng
- , Zhendong Zheng
- & Ruijun Tian
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