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| Open AccessSensing their plasma membrane curvature allows migrating cells to circumvent obstacles
Motile cells must navigate complex environments. Here the authors use state-of-the-art imaging, coarse-grained MD simulations and experimental biophysics to show that cells sense their plasma membrane curvature to circumvent obstacles.
- Ewa Sitarska
- , Silvia Dias Almeida
- & Alba Diz-Muñoz
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Article
| Open AccessExperimental and theoretical model for the origin of coiling of cellular protrusions around fibers
The leading edges of cellular protrusions coil around extracellular fibers and other fibrous structures such as axons. Combining 3D imaging with theoretical models, the authors show that coiling occurs naturally on curved surfaces due to energy minimization.
- Raj Kumar Sadhu
- , Christian Hernandez-Padilla
- & Nir S. Gov
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Article
| Open AccessThe H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease
SARS-CoV-2 main protease adapts a disulfide bonded inactive state to escape oxidative stress. Here, the authors report a crystal structure of an inactive conformation of the enzyme achieved through a H163A mutation, and the mechanistic details of conformational changes using atomistic simulations.
- Norman Tran
- , Sathish Dasari
- & Aravindhan Ganesan
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| Open AccessExploring non-equilibrium processes and spatio-temporal scaling laws in heated egg yolk using coherent X-rays
The soft-grainy microstructure of cooked egg yolk is the result of a series of out of equilibrium processes of its protein-lipid contents. Here, the authors develop a time-temperature phase diagram that shows the coupling of the nanoscale processes that result in the grainy-gel microstructure of cooked egg yolk.
- Nimmi Das Anthuparambil
- , Anita Girelli
- & Christian Gutt
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Article
| Open AccessBuilding block aspect ratio controls assembly, architecture, and mechanics of synthetic and natural protein networks
Fibrous networks constructed from high aspect ratio protein building blocks are ubiquitous in nature, but the functional advantage of such building blocks over globular proteins is not understood. Here, using shear rheology and small-angle neutron scattering, the authors characterise the mechanical and structural properties of photochemically crosslinked protein L and fibrin networks and show that aspect ratio is a crucial property that defines network architecture and mechanics.
- Matt D. G. Hughes
- , Sophie Cussons
- & Lorna Dougan
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Article
| Open AccessMulti-scale dynamic imaging reveals that cooperative motility behaviors promote efficient predation in bacteria
Myxococcus xanthus forages and moves collectively to prey and feed on other bacterial species. Here, the authors challenge the conventional idea that during Myxococcus xanthus predation, A- and S-motilities are limited to specific forager and swarm roles and reveal a synergistic interaction between these motilities to enhance predation efficiency.
- Sara Rombouts
- , Anna Mas
- & Marcelo Nollmann
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Article
| Open AccessExtracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4
Dying cells display an “eat me” signal through phospholipid scrambling. Here, the authors show that activation of the plasma membrane-bound Xkr4 scramblase requires extracellular calcium as a “molecular glue” for connecting transmembrane regions.
- Panpan Zhang
- , Masahiro Maruoka
- & Jun Suzuki
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Article
| Open AccessGeometric alignment of aminoacyl-tRNA relative to catalytic centers of the ribosome underpins accurate mRNA decoding
Protein synthesis is dependent on the ribosome’s ability to accurately select tRNA. Molecular simulations reveal divergent pathways for correct and incorrect tRNA during selection, indicating that tRNA alignment is key to protein production.
- Dylan Girodat
- , Hans-Joachim Wieden
- & Karissa Y. Sanbonmatsu
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Article
| Open AccessPhase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions
Mixtures of prion-like low complexity domains (PLCDs) are found in condensates such as stress granules. In this work, the authors report how the interplay between homotypic and heterotypic interactions contributes to condensate formation by mixtures of PLCDs.
- Mina Farag
- , Wade M. Borcherds
- & Rohit V. Pappu
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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 AccessDirect observation of tRNA-chaperoned folding of a dynamic mRNA ensemble
T-box riboswitch RNAs directly bind to specific tRNA and regulate the transcription or translation of downstream genes in bacteria. Using single-molecule FRET and ensemble biophysical analyses, here the authors uncover a Venus flytrap-like mechanism where tRNA binding to a T-box riboswitch mRNA triggers its rapid domain closure.
- Krishna C. Suddala
- , Janghyun Yoo
- & Jinwei Zhang
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Article
| Open AccessVisualizing the membrane disruption action of antimicrobial peptides by cryo-electron tomography
Antimicrobial peptide mechanism of membrane disruption have not been fully characterized at the cellular level. Here, authors use cryo-electron tomography and AFM to directly visualize the disruption of the outer and inner membranes of Escherichia coli by a de novo-designed peptide.
- Eric H.-L. Chen
- , Chun-Hsiung Wang
- & Rita P.-Y. Chen
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Article
| Open AccessMethylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology
Aberrant liquid-to-gel transition of biological condensates can lead to pathological fibrillization and disease. Here, the authors demonstrate that a small molecule, methylene blue, can decouple gelation from fibrillization of tau liquid droplets.
- Yongqi Huang
- , Jitao Wen
- & Meng Gao
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Article
| Open AccessControl of intracellular pH and bicarbonate by CO2 diffusion into human sperm
Bicarbonate (HCO3−) is critical in sperm for stimulation of cAMP synthesis during fertilization, though there is dispute over how HCO3− is transported into sperm. Here the authors use limit-of-detection LC/MS to characterize sperm protein expression and show that HCO3− is produced from CO2 diffusion into sperm rather than active transport.
- Elena Grahn
- , Svenja V. Kaufmann
- & U.Benjamin Kaupp
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Article
| Open AccessCoordinated peptidoglycan synthases and hydrolases stabilize the bacterial cell wall
The integrity and maintenance of cell-wall peptidoglycan is essential for growth and cell shape in bacteria. Here, the authors show how the coordinated actions of a synthase, which inserts new peptidoglycan strands, and a hydrolase, which generates openings to allow the insertion, determine the integrity of bacterial cell wall.
- Huan Zhang
- , Srutha Venkatesan
- & Beiyan Nan
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Article
| Open AccessFAP106 is an interaction hub for assembling microtubule inner proteins at the cilium inner junction
Microtubule inner proteins (MIPs) contribute to species-specific motility characteristics but are largely unstudied. Here, the authors combine functional, structural and proteomic analysis in T. brucei to advance fundamental understanding of MIP assembly and identify trypanosome-specific MIPs required for motility.
- Michelle M. Shimogawa
- , Angeline S. Wijono
- & Kent L. Hill
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Article
| Open AccessStructural basis for the allosteric modulation of rhodopsin by nanobody binding to its extracellular domain
G protein-coupled receptors (GPCRs) are involved in many physiological processes and are targets of intense drug discovery research. Here, the authors describe llama-derived nanobodies that allosterically modulate rhodopsin, a prototypical GPCR.
- Arum Wu
- , David Salom
- & Krzysztof Palczewski
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Article
| Open AccessStructural and functional insights into the modulation of T cell costimulation by monkeypox virus protein M2
The B7 family proteins B7.1 (CD80) and B7.2 (CD86) are two well-studied costimulatory ligands that play critical roles in host T cell immunity against viral infection. In this study, the authors show that oligomeric M2 protein encoded by monkeypox virus serves as a viral decoy receptor and inhibits T cell activation mediated by hB7.1/2 co-stimulation via the blockade of CD28 binding to human B7.1/2, providing molecular mechanisms of poxvirus M2 function and immune evasion.
- Shangyu Yang
- , Yong Wang
- & Haiyan Zhao
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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 AccessStructural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13
Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Here, the authors report crystal structures of HSD17B13 and its complexes with two series of inhibitors.
- Shenping Liu
- , Ruth F. Sommese
- & Michelle F. Clasquin
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Article
| Open AccessThermodynamic principle to enhance enzymatic activity using the substrate affinity
Currently, there is no well-defined strategy to increase the activity of enzymes. Here, the authors provide mathematical evidence that adjusting the Michaelis-Menten constant to the substrate concentration maximizes enzymatic activity.
- Hideshi Ooka
- , Yoko Chiba
- & Ryuhei Nakamura
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Article
| Open AccessSwitch of cell migration modes orchestrated by changes of three-dimensional lamellipodium structure and intracellular diffusion
How do cells regulate their migration speed and direction? Here, authors discover that keratocyte cells can reversibly switch between different migration modes, by changing the 3D lamellipodium shape and intracellular diffusion.
- Chao Jiang
- , Hong-Yu Luo
- & Hui Li
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Article
| Open AccessMolecular architecture and conservation of an immature human endogenous retrovirus
The hexagonal immature capsid lattice of human endogenous retrovirus K is determined at 3.2 Å resolution, which is an assembly of small molecule-stabilized hexamers via dimer and trimer interfaces, a highly conserved mechanism among retroviruses.
- Anna-Sophia Krebs
- , Hsuan-Fu Liu
- & Peijun Zhang
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Article
| Open AccessStable trapping of multiple proteins at physiological conditions using nanoscale chambers with macromolecular gates
The possibility to trap biomolecules is important for analysing them by optical methods. Here we show how nanoscale chambers with macromolecular gates can be used to trap hundreds of proteins in a volume of one attoliter at physiological conditions without exposing them to any direct forces.
- Justas Svirelis
- , Zeynep Adali
- & Andreas Dahlin
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Article
| Open AccessStructural insights into opposing actions of neurosteroids on GABAA receptors
Legesse et al. present structural studies of a human GABAA receptor in complex with positive and negative modulator neurosteroids, uncovering mechanisms of potentiation and inhibition.
- Dagimhiwat H. Legesse
- , Chen Fan
- & Ryan E. Hibbs
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Article
| Open AccessA mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels
Here, authors have identified two pairs of large hydrophobic residues in the channel S6 segments that form the inactivation gate of eukaryotic Na+ channels.
- Yichen Liu
- , Carlos A. Z. Bassetto Jr
- & Francisco Bezanilla
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Article
| Open AccessRedox driven B12-ligand switch drives CarH photoresponse
CarH is a bacterial B12-binding photoreceptor involved in transcriptional regulation. Here, the authors provide insights into B12 dynamics and associated cobalt redox changes following light activation. These demonstrate the CarH response integrates light and oxygen sensing.
- Harshwardhan Poddar
- , Ronald Rios-Santacruz
- & David Leys
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Article
| Open AccessThe net electrostatic potential and hydration of ABCG2 affect substrate transport
ABCG2, an ATP-binding cassette transporter, extrudes hundreds of hydrophilic and hydrophobic compounds from cells, playing roles in xenobiotic clearance or multidrug resistance in cancer. Gose et al provide key insights into ABCG2 substrate selection.
- Tomoka Gose
- , Heather M. Aitken
- & John D. Schuetz
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Article
| Open AccessCrystal structures of MHC class I complexes reveal the elusive intermediate conformations explored during peptide editing
The unusual crystal structures of MHC I-peptide complexes provide a visualization of the remarkable ability of the groove to adapt conformationally to bound peptides, explaining how MHC I molecules edit peptides in antigen presentation.
- Lenong Li
- , Xubiao Peng
- & Marlene Bouvier
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Article
| Open AccessLigand recognition and G protein coupling of the human itch receptor MRGPRX1
MRGPRX1 is a key GPCR expressed in the DRG for itch perception, generating scratch or avoidance behaviors. Here, authors provide structural and pharmacological insights into itch sensation, activation and G-protein signaling downstream of MRGPRX1.
- Lulu Guo
- , Yumu Zhang
- & Jin-Peng Sun
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Article
| Open AccessMulticolor lifetime imaging and its application to HIV-1 uptake
Multicolor imaging employing genetically-encodable fluorescent proteins permits spatiotemporal live cell imaging of multiple cues. Here, authors use multicolor lifetime imaging to visualize quadruple-labelled human immunodeficiency viruses within cellular contexts.
- Tobias Starling
- , Irene Carlon-Andres
- & Sergi Padilla-Parra
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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 AccessMolecular mechanism underlying regulation of Arabidopsis CLCa transporter by nucleotides and phospholipids
CLC transporters are regulated by nucleotides and phospholipids. Here cryo-EM structure of Arabidopsis CLCa in complex with ATP and PIP2 and electrophysiological analysis suggests the underlying regulatory mechanisms of both nucleotides and phospholipids.
- Zhao Yang
- , Xue Zhang
- & Peng Zhang
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Article
| Open AccessIdentification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase
TMEM16F is a Ca2+ activated ion channel and lipid scramblase involved in cell fusion. Here authors determine cryo-EM structures of TMEM16F with or without bound blockers, such as the FDA-approved drug niclosamide.
- Shengjie Feng
- , Cristina Puchades
- & Lily Yeh Jan
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Article
| Open AccessStructural basis of agonist specificity of α1A-adrenergic receptor
α1-adrenergic receptors (α1- AR) play critical roles in the cardiovascular and nervous systems. Here, the authors report molecular insights into the mechanisms underlying the discrimination between α1A-AR and α1B-AR by the agonist A61603.
- Minfei Su
- , Jinan Wang
- & Xin-Yun Huang
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Matters Arising
| Open AccessAntibiotics and hexagonal order in the bacterial outer membrane
- Georgina Benn
- , Thomas J. Silhavy
- & Bart W. Hoogenboom
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Article
| Open AccessCryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn2+ uptake into the Golgi apparatus
ZnT7 is a Golgi-localized Zn2 + /H+ antiporter. Here the authors present the cryo-EM structures of human ZnT7 in Zn2 + -bound and unbound forms, shedding light on its mechanism of Zn2+ transport.
- Han Ba Bui
- , Satoshi Watanabe
- & Kenji Inaba
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Article
| Open AccessMolecular basis of Mg2+ permeation through the human mitochondrial Mrs2 channel
Mrs2 is a mitochondrial Mg2+ channel that is essential for metabolic function. Here, the authors present cryo-EM structures of human Mrs2 revealing symmetrical pentameric assembly and how Mrs2 permeates Mg2+.
- Ming Li
- , Yang Li
- & Yuequan Shen
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Article
| Open AccessControl of motor landing and processivity by the CAP-Gly domain in the KIF13B tail
Intracellular transport of material along microtubules by kinesin motors is critical for cellular homeostasis. Here the authors uncover a unique role for a specialized kinesin tail domain in directing motor transport along specific microtubule tracks.
- Xiangyu Fan
- & Richard J. McKenney
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Article
| Open AccessMembrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor
The AT1 GPCR plays an essential role in cardiovascular regulation and may be activated by the peptide AngII as well as membrane stretch. Here, Poudel et al. use molecular simulations to show that membrane-mediated activation produces distinct active-like conformations when compared to activation by AngII.
- Bharat Poudel
- , Rajitha Rajeshwar T
- & Juan M. Vanegas
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Article
| Open AccessNetwork-wide thermodynamic constraints shape NAD(P)H cofactor specificity of biochemical reactions
NADH and NADPH are redox cofactors coexisting in all living cells. Here, the authors present a computational study suggesting that evolved NAD(P)H reaction specificities in E. coli are largely shaped by metabolic network structure enabling maximal thermodynamic driving forces close to the theoretical optimum.
- Pavlos Stephanos Bekiaris
- & Steffen Klamt
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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 AccessDeterministic early endosomal maturations emerge from a stochastic trigger-and-convert mechanism
Newly formed endosomes mature into early endosomes by shedding one protein and acquiring another. Here, the authors describe a trigger-and-convert mechanism driven by endosomal collisions and fusions that govern timeliness in ensemble maturations.
- Harrison M. York
- , Kunaal Joshi
- & Senthil Arumugam
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Article
| Open AccessEnergetic robustness to large scale structural fluctuations in a photosynthetic supercomplex
Robust photosynthetic light harvesting occurs in large membrane supercomplexes. Here, the authors show that supercomplexes occupy an unexpectedly large range of conformations yet maintain their efficiency due to specific, critical chlorophylls.
- Dvir Harris
- , Hila Toporik
- & Yuval Mazor
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Article
| Open AccessConformational changes in the essential E. coli septal cell wall synthesis complex suggest an activation mechanism
The divisome is a macromolecular machine composed of more than 30 proteins that controls cell wall constriction during bacterial cell division. Here, the authors provide insights into the structure and dynamics of the divisome core complex using a combination of structure prediction, molecular dynamics simulation, single-molecule imaging, and mutagenesis.
- Brooke M. Britton
- , Remy A. Yovanno
- & Zach Hensel
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Article
| Open AccessPartition complex structure can arise from sliding and bridging of ParB dimers
In many bacteria and plasmids, DNA segregation is controlled by the ParABS system, an essential component of which is the formation of a nucleoprotein complex. Here, making use of recent discoveries, the authors develop a sliding and bridging model to predict the fine structure of this complex.
- Lara Connolley
- , Lucas Schnabel
- & Seán M. Murray
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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 AccessIon selectivity and rotor coupling of the Vibrio flagellar sodium-driven stator unit
In this work, the authors provide mechanistic insights for understanding the sodium-dependent, bacterial flagellar stator unit PomAB ion selectivity, directional rotation, and rotor incorporation in Vibrio spp.
- Haidai Hu
- , Philipp F. Popp
- & Nicholas M. I. Taylor
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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