Mechanism of action articles within Nature Communications

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  • Article
    | Open Access

    Unbiased chemical biology strategies for direct readout of small molecule protein interactomes provide advantages over target-focused approaches. Here, the authors describe the BioTAC system, a network-scale small molecule guided proximity labeling platform, to rapidly identify ligand-target interactomes.

    • Andrew J. Tao
    • , Jiewei Jiang
    •  & Fleur M. Ferguson
  • Article
    | Open Access

    Vibrio α-hemolysins (αHLs) are toxins crucial for certain bacterial infections. Here the authors reveal that calcium ions boost the activity of a specific toxin, Vibrio campbellii αHL, and uncover its calcium-dependent activation mechanism.

    • Yu-Chuan Chiu
    • , Min-Chi Yeh
    •  & Shih-Ming Lin
  • Article
    | Open Access

    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
  • Article
    | Open Access

    The mechanism of action of the antibacterial tripeptide AMC-109 is unclear. Here, Melcrová et al. show that AMC-109 self-assembles into stable aggregates with a cationic surface, and then individual peptides insert into the bacterial membrane and disrupt membrane nanodomains, thus affecting membrane function without forming pores.

    • Adéla Melcrová
    • , Sourav Maity
    •  & Wouter H. Roos
  • Article
    | Open Access

    The aryl hydrocarbon receptor regulates the expression of genes involved in many cell processes and its dysregulation has been implicated in different diseases. Here, the authors identify dietary monoterpenoid carvone as an atypical non-competitive antagonist of human aryl hydrocarbon receptor and demonstrate that it can protect against ultraviolet skin damage in female mice.

    • Karolína Ondrová
    • , Iveta Zůvalová
    •  & Zdeněk Dvořák
  • Article
    | Open Access

    Rapid antibiotic resistance in bacteria is putting pressure on both existing therapies as well as the development pipeline. Here, the authors present a dual-acting anti-virulence treatment that evades antibiotic resistance mechanisms and remains effective against Top Priority pathogens.

    • Christopher Jonkergouw
    • , Ngong Kodiah Beyeh
    •  & Markus B. Linder
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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 Access

    In this manuscript the authors report accurate multi-state protein structures of the PDZ domain using biological NMR. By looking into protein structural states, the authors report an allosteric pathway at atomic resolution that validates previously reported low resolution findings and uncovered a structural hallmark of the allosteric ligand binding to the PDZ domain.

    • Dzmitry Ashkinadze
    • , Harindranath Kadavath
    •  & Roland Riek
  • Article
    | Open Access

    Managing herbicide resistance problem needs the identification of new herbicidal modes of action. Here, the authors solve the crystal structures of Arabidopsis HMGR and show HMGR as a potential new herbicide target by identifying plant-specific HMGR inhibitors and engineering tolerant trait in Arabidopsis.

    • Joel Haywood
    • , Karen J. Breese
    •  & Joshua S. Mylne
  • Article
    | Open Access

    The catalytic activity of regenerable nanozymes is currently the bottle neck for their wider employment. Here, the authors report on single-atom nanozymes of RhN4, VN4, and Fe-Cu-N6 with higher catalytic activities than natural enzymes, and demonstrate the Rh/VN4 recyclability and scalp healing properties in bioactive sutures.

    • Shaofang Zhang
    • , Yonghui Li
    •  & Xiao-Dong Zhang
  • Article
    | Open Access

    Several strategies have been developed in recent years for therapeutic induction of ferroptosis in cancer. Here the authors report the design of two hypercarbon-centered gold(I) cluster prodrugs that induce ferroptosis of cancer cells, showing anti-tumor activity in preclinical bladder cancer models.

    • Kui Xiao
    • , Niyuan Zhang
    •  & Liang Zhao
  • Article
    | Open Access

    Gomez-Sintes et al. have developed small molecules that selectively activate chaperone-mediated autophagy by stabilizing the interaction between retinoic acid receptor alpha and its co-repressor N-CoR1. They demonstrate the protective effect of boosting chaperone-mediated autophagy against retinal degeneration.

    • Raquel Gomez-Sintes
    • , Qisheng Xin
    •  & Ana Maria Cuervo
  • Article
    | Open Access

    The current peripherally acting mu-opioid receptor antagonists present limited permeability and pharmacokinetic properties. Here, the authors develop a drug delivery approach based on AG10, which demonstrates the impact of mu-opioid receptors in the central nervous system in precipitating opioid-induced constipation.

    • Md Tariqul Haque Tuhin
    • , Dengpan Liang
    •  & Mamoun M. Alhamadsheh
  • Article
    | Open Access

    Fatty acid unsaturation by stearoyl-CoA desaturase 1 (SCD1) protects against cellular stress through unclear mechanisms. Here the authors show 1,2-dioleoyl-sn-glycero-3-phospho-(1’-myo-inositol) is an SCD1-derived signaling lipid that regulates stress-adaption, protects against cell death and promotes proliferation.

    • Maria Thürmer
    • , André Gollowitzer
    •  & Andreas Koeberle
  • Article
    | Open Access

    Light-oxygen-voltage (LOV) photoreceptors perceive blue light to elicit spatio-temporally defined cellular responses, and their signalling process has been extensively characterized. Here the authors report that the light signal is still transduced in the absence of a conserved Gln residue, thought to be key.

    • Julia Dietler
    • , Renate Gelfert
    •  & Andreas Möglich
  • Article
    | Open Access

    Whether hypoxia-inducible factors (HIFs) can be directly regulated by endogenous small molecules is a long-standing question. Here authors identified the metabolite oleoylethanolamide as a HIF-3α ligand and further revealed its mechanism of action.

    • Xiaotong Diao
    • , Fei Ye
    •  & Dalei Wu
  • Article
    | Open Access

    Here, de Vries et al. perform a pre-clinical characterization of the antimalarial compound MMV693183: the compound targets acetyl-CoA synthetase, has efficacy in humanized mice against Plasmodium falciparum infection, blocks transmission to mosquito vectors, is safe in rats, and pharmacokinetic-pharmacodynamic modeling informs about a potential oral human dosing regimen.

    • Laura E. de Vries
    • , Patrick A. M. Jansen
    •  & Koen J. Dechering
  • Article
    | Open Access

    Molecular glue has been used as a broad term describing a class of protein interaction-promoting compounds. Here, the authors outline two unifying thermodynamic features to formally define molecular glues and guide their prospective discovery.

    • Shiyun Cao
    • , Shoukai Kang
    •  & Ning Zheng
  • Article
    | Open Access

    The mechanism-of-action of many electrohilic drugs remains poorly understood. Here, the authors use a redox-targeting approach to elucidate the basis for the innate immune cell toxicity of dimethyl fumarate, showing that it modifies Keap1 to trigger mitochondrial-targeted neutrophil/macrophage apoptosis.

    • Jesse R. Poganik
    • , Kuan-Ting Huang
    •  & Yimon Aye
  • Article
    | Open Access

    Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.

    • Yi Yang
    • , Adam Csakai
    •  & Hang Yin
  • Article
    | Open Access

    The intracellular compartment is a crowded environment. Here, the authors use molecular dynamics (MD) simulations to assess inhibitor binding to c-Src kinase and show how ligand binding pathways differ in crowded and dilute protein solutions, highlighting the role of c-Src Tyr82 sidechain.

    • Kento Kasahara
    • , Suyong Re
    •  & Yuji Sugita
  • Article
    | Open Access

    The membrane is an integral component of the G protein-coupled receptor signaling machinery. Here authors demonstrate that lipids regulate the signaling efficacy and selectivity of the ghrelin receptor GHSR through specific interactions and bulk effects and observe PIP2 and GM3 induced shifts of the conformational equilibrium of GHSR away from its inactive state.

    • Marjorie Damian
    • , Maxime Louet
    •  & Jean-Louis Banères
  • Article
    | Open Access

    The detailed mechanisms of action of bactericidal antibiotics remain unclear. Here, Wong et al. show that these antibiotics induce cytoplasmic condensation through membrane damage and outflow of cytoplasmic contents, as well as accumulation of reactive metabolic by-products and lipid peroxidation, as part of their lethality.

    • Felix Wong
    • , Jonathan M. Stokes
    •  & James J. Collins
  • Article
    | Open Access

    Aminoglycoside antibiotics target the ribosome and induce misreading, yet which translation errors induce bacterial cell death is unclear. Here authors use quantitative mass spectrometry and show that bactericidal aminoglycosides induce clusters of errors in full-length proteins in vivo with as many as four amino acid substitutions in a row.

    • Ingo Wohlgemuth
    • , Raffaella Garofalo
    •  & Marina V. Rodnina
  • Article
    | Open Access

    Reveromycin A (RM-A) selectively inhibits eukaryotic cytoplasmic isoleucyltRNA synthetase (IleRS). Herein, the authors show that RM-A molecule occupies the tRNAIle binding site of Saccharomyces cerevisiae IleRS, and that RM-A cooperates with isoleucine or isoleucyl-adenylate for IleRS binding.

    • Bingyi Chen
    • , Siting Luo
    •  & Huihao Zhou
  • Article
    | Open Access

    TNF can be inhibited by small molecules that stabilize the TNF trimer in an asymmetric conformation. Here, the authors develop a monoclonal antibody that selectively binds this inactive form of TNF, enabling both target engagement assessment and structural characterization of TNF binding to TNF receptor 1.

    • Daniel J. Lightwood
    • , Rebecca J. Munro
    •  & Alastair D. G. Lawson
  • Article
    | Open Access

    The drug-like compound PF846 and its derivatives inhibit the translation of specific mRNAs by the human ribosome. Here the authors show how PF846 arrests translation at the stop codon by slowing hydrolysis of the protein nascent chain at the ribosome P-site tRNA by eukaryotic release factor 1 (eRF1).

    • Wenfei Li
    • , Stacey Tsai-Lan Chang
    •  & Jamie H. D. Cate
  • Article
    | Open Access

    5-hydroxythalidomide is a primary thalidomide metabolite generated by the cytochrome P450 isozymes. The reported data, including crystal structure of the 5-hydroxythalidomide-mediated complex of CRBN with SALL4, elucidate how additional hydroxy group of the metabolite enhances the interaction of CRBN with the neosubstrate SALL4.

    • Hirotake Furihata
    • , Satoshi Yamanaka
    •  & Takuya Miyakawa
  • Article
    | Open Access

    Antibiotics targeting protein translation interact in hard-to-predict ways. Here, Kavčič et al. interpret these interactions in terms of translation bottlenecks, the kinetics of drug uptake and target binding, bacterial growth laws, and a model of queued traffic progression.

    • Bor Kavčič
    • , Gašper Tkačik
    •  & Tobias Bollenbach
  • Article
    | Open Access

    Small molecule stabilizers of protein–protein interactions hold great therapeutic potential. Based on virtual screening and molecular docking, the authors here develop a strategy to evolve weak, promiscuous inhibitors of 14-3-3 interactions into selective stabilizers of the 14-3-3/ChREBP complex.

    • Eline Sijbesma
    • , Emira Visser
    •  & Christian Ottmann
  • Article
    | Open Access

    Upon transition to stationary phase or upon stress, bacteria limit protein synthesis through small inhibitory proteins that bind the ribosome. Here the authors decipher the interaction mode of the bacterial ribosome silencing factor (RsfS) at atomic details to provide an in depth view of how it shutdowns ribosomes.

    • Iskander Khusainov
    • , Bulat Fatkhullin
    •  & Marat Yusupov
  • Article
    | Open Access

    Bacillus thuringiensis israelensis (Bti) produces the naturally-crystalline proteinaceous toxin Cyt1Aa that is toxic to mosquito larvae. Here the authors grow recombinant nanocrystals of the Cyt1Aa protoxin in vivo and use serial femtosecond crystallography to determine its structure at different redox and pH conditions and by combining their structural data with further biochemical, toxicological and biophysical analyses provide mechanistic insights into the Cyt1Aa bioactivation cascade.

    • Guillaume Tetreau
    • , Anne-Sophie Banneville
    •  & Jacques-Philippe Colletier
  • Article
    | Open Access

    Formylpeptide receptors (FPRs) are a class of chemotactic G protein-coupled receptors (GPCRs) that recognize pathogen- and host-derived formylpeptides. Here the authors report the 3.17 Å cryo-EM structure of the human FPR2-Gi signaling complex with a bound peptide agonist and in combination with computational docking and MD simulations provide mechanistic insights into formylpeptide recognition by FPRs.

    • Youwen Zhuang
    • , Heng Liu
    •  & Cheng Zhang
  • Article
    | Open Access

    The biology of Alzheimer’s disease (AD) remains unknown. We propose AD is a protein connectivity-based dysfunction disorder whereby a switch of the chaperome into epichaperomes rewires proteome-wide connectivity, leading to brain circuitry malfunction that can be corrected by novel therapeutics.

    • Maria Carmen Inda
    • , Suhasini Joshi
    •  & Gabriela Chiosis
  • Article
    | Open Access

    The ERK signalling pathway is activated in many cancers, however ERK1 and ERK2 are difficult to target pharmacologically. Here, the authors identify a small molecule inhibitor that binds covalently to the D-recruitment site of ERK and induces cell death and reduces tumour growth in mice.

    • Tamer S. Kaoud
    • , William H. Johnson
    •  & Kevin N. Dalby
  • Article
    | Open Access

    Osh6p and Osh7p are yeast lipid transfer proteins (LTPs) that must transiently interact with membranes but how they escape from the electrostatic attraction of the plasma membrane is unclear. Here authors show that Osh6p reduces its avidity for anionic membranes once it captures PS or PI4P, due to a molecular lid closing its lipid-binding pocket.

    • Nicolas-Frédéric Lipp
    • , Romain Gautier
    •  & Guillaume Drin
  • Article
    | Open Access

    Curaxins are a recently discovered class of anti-cancer agents that disturbs DNA/histone interactions within. Here the authors provide evidence that curaxins affect the spatial genome organization and compromise enhancer-promoter communication necessary for expression of several oncogenes, including MYC.

    • Omar L. Kantidze
    • , Artem V. Luzhin
    •  & Sergey V. Razin
  • Article
    | Open Access

    PROTACs enable targeted protein degradation by recruiting an E3 ligase to a specific substrate but the determinants of selectivity are not fully understood. Here, the authors show that varying the linker between warhead and E3 ligand and the orientation of the E3 ligase allow tuning PROTAC selectivity toward different p38 isoforms.

    • Blake E. Smith
    • , Stephen L. Wang
    •  & Craig M. Crews