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2 results on '"Dept Mol Pharmacol Physiol '

1. A Novel Type V TA System Where mRNA for Toxin GhoT is Cleaved by Antitoxin GhoS

Author

Kevin Zheng, Rebecca Page, Viviana Sanchez-Torres, Xiaoxue Wang, Dana M. Lord, Wolfgang Peti, Seok Hoon Hong, Thomas K. Wood, Cecilia Quiroga, Hsin Yao Cheng, Michael J. Benedik, Torsten Herrmann, Devon O. Osbourne, Key Lab Marine Bioresources Sustainable Utilizat, Chinese Academy of Sciences [Beijing] (CAS), Dept Chem Engn, Texas A&M University [College Station], Dept Mol Pharmacol Physiol & Biotechnol, Brown University, Pennsylvania State University (Penn State), Penn State System-Penn State System, Dept Mol Biol Cell Biol & Biochem, ISA - Centre de RMN à très hauts champs, Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Dept Biol, Texas A&M University [College Station]-Texas A&M University System, Dept Biochem & Mol Biol, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania State University (Penn State), US National Institutes of Health (R01 GM089999 ), US National Science Foundation (CAREER award MCB 0952550), and 1000-Youth Elite Program from China.

Subjects
EXPRESSION, Protein Conformation, RNase P, NMR STRUCTURE DETERMINATION, Bacterial Toxins, PROTEIN, Biology, medicine.disease_cause, MULTIDRUG TOLERANCE, Article, GhoT/GhoS, Persistence, 03 medical and health sciences, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, medicine, RNA, Messenger, Nuclear Magnetic Resonance, Biomolecular, Molecular Biology, Escherichia coli, 030304 developmental biology, Alanine, 0303 health sciences, Messenger RNA, Reverse Transcriptase Polymerase Chain Reaction, 030306 microbiology, Toxin, Hydrolysis, BIOFILM FORMATION, RNA, GENERAL STRESS-RESPONSE, Cell Biology, Toxin-antitoxin system, Molecular biology, Toxin/antitoxin, Biochemistry, ESCHERICHIA-COLI, Biofilms, CELLS, BACTERIAL PERSISTENCE, Antitoxins, Antitoxin, REGULATOR
Abstract

International audience; Among bacterial toxin-antitoxin systems, to date no antitoxin has been identified that functions by cleaving toxin mRNA. Here we show that YjdO (renamed GhoT) is a membrane lytic peptide that causes ghost cell formation (lysed cells with damaged membranes) and increases persistence (persister cells are tolerant to antibiotics without undergoing genetic change). GhoT is part of a new toxin-antitoxin system with YjdK (renamed GhoS) because in vitro RNA degradation studies, quantitative real-time reverse-transcription PCR and whole-transcriptome studies revealed that GhoS masks GhoT toxicity by cleaving specifically yjdO (ghoT) mRNA. Alanine substitutions showed that Arg28 is important for GhoS activity, and RNA sequencing indicated that the GhoS cleavage site is rich in U and A. The NMR structure of GhoS indicates it is related to the CRISPR-associated-2 RNase, and GhoS is a monomer. Hence, GhoT-GhoS is to our knowledge the first type V toxin-antitoxin system where a protein antitoxin inhibits the toxin by cleaving specifically its mRNA.

Published
2012

2. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor

Author

Malene Ringkjøbing Jensen, Wolfgang Peti, Dorothy Koveal, Sai Dipikaa Akshinthala, Daniel H. Miller, Carla-Maria Gauss, Nicholas K. Tonks, Senthil K. Muthuswamy, Martin Blackledge, Navasona Krishnan, Jaka Kragelj, Rebecca Page, Bin Xue, UCL Institute of Neurology, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Dept Mol Pharmacol Physiol & Biotechnol, Brown University, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Thomas, Frank

Subjects
Models, Molecular, MESH: Signal Transduction, Receptor, ErbB-2, MESH: Protein Structure, Secondary, MESH: Catalytic Domain, Plasma protein binding, MESH: Allosteric Regulation, Protein Structure, Secondary, Metastasis, Mice, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Protein structure, Catalytic Domain, MESH: Molecular Targeted Therapy, MESH: Animals, Molecular Targeted Therapy, MESH: Spermine, MESH: Allosteric Site, MESH: Cholestanes, Protein Tyrosine Phosphatase, Non-Receptor Type 1, 0303 health sciences, MESH: Kinetics, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Gene Expression Regulation, Neoplastic, Small molecule, 3. Good health, Cell biology, Gene Expression Regulation, Neoplastic, MESH: Receptor, ErbB-2, Biochemistry, 030220 oncology & carcinogenesis, Female, Signal transduction, Allosteric Site, hormones, hormone substitutes, and hormone antagonists, MESH: Models, Molecular, Protein Binding, Signal Transduction, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Allosteric regulation, MESH: Mammary Neoplasms, Experimental, Antineoplastic Agents, Breast Neoplasms, Biology, Article, 03 medical and health sciences, Allosteric Regulation, medicine, Animals, Humans, MESH: Protein Binding, Binding site, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, Cholestanes, Mammary Neoplasms, Experimental, Active site, Cell Biology, medicine.disease, Protein Structure, Tertiary, MESH: Protein Tyrosine Phosphatase, Non-Receptor Type 1, Kinetics, biology.protein, MESH: Antineoplastic Agents, Spermine, MESH: Female, MESH: Breast Neoplasms
Abstract

International audience; PTP1B, a validated therapeutic target for diabetes and obesity, has a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We define a new mechanism of allosteric inhibition that targets the C-terminal, noncatalytic segment of PTP1B. We present what is to our knowledge the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small-molecule inhibitor MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules.

Published
2014

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