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Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design.
Dong, Yin Yao; Wang, Hua; Pike, Ashley C W; Cochrane, Stephen A; Hamedzadeh, Sadra; Wyszynski, Filip J; Bushell, Simon R; Royer, Sylvain F; Widdick, David A; Sajid, Andaleeb; Boshoff, Helena I; Park, Yumi; Lucas, Ricardo; Liu, Wei-Min; Lee, Seung Seo; Machida, Takuya; Minall, Leanne; Mehmood, Shahid; Belaya, Katsiaryna; Liu, Wei-Wei; Chu, Amy; Shrestha, Leela; Mukhopadhyay, Shubhashish M M; Strain-Damerell, Claire; Chalk, Rod; Burgess-Brown, Nicola A; Bibb, Mervyn J; Barry Iii, Clifton E; Robinson, Carol V; Beeson, David; Davis, Benjamin G; Carpenter, Elisabeth P.
Afiliação
  • Dong YY; Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
  • Wang H; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK.
  • Pike ACW; Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
  • Cochrane SA; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK; School of Chemistry and Chemical Engineering, Queen's University, Belfast, UK.
  • Hamedzadeh S; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK.
  • Wyszynski FJ; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK.
  • Bushell SR; Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
  • Royer SF; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK.
  • Widdick DA; Department of Molecular Microbiology, John Innes Centre, Norwich, NR4 7UH, UK.
  • Sajid A; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Boshoff HI; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Park Y; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Lucas R; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK.
  • Liu WM; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK.
  • Lee SS; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK.
  • Machida T; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK.
  • Minall L; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK.
  • Mehmood S; Department of Chemistry, Oxford, OX1 3QZ, UK.
  • Belaya K; Neurosciences Group, Nuffield Department of Clinical Neuroscience, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
  • Liu WW; Neurosciences Group, Nuffield Department of Clinical Neuroscience, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
  • Chu A; Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
  • Shrestha L; Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
  • Mukhopadhyay SMM; Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
  • Strain-Damerell C; Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
  • Chalk R; Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
  • Burgess-Brown NA; Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.
  • Bibb MJ; Department of Molecular Microbiology, John Innes Centre, Norwich, NR4 7UH, UK.
  • Barry Iii CE; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • Robinson CV; Department of Chemistry, Oxford, OX1 3QZ, UK.
  • Beeson D; Neurosciences Group, Nuffield Department of Clinical Neuroscience, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
  • Davis BG; Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK. Electronic address: Ben.Davis@chem.ox.ac.uk.
  • Carpenter EP; Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK. Electronic address: liz.carpenter@sgc.ox.ac.uk.
Cell ; 175(4): 1045-1058.e16, 2018 11 01.
Article em En | MEDLINE | ID: mdl-30388443
ABSTRACT
Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic "lipid-altered" tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: N-Acetilglucosaminiltransferases / Defeitos Congênitos da Glicosilação / Inibidores Enzimáticos / Antibióticos Antituberculose Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: N-Acetilglucosaminiltransferases / Defeitos Congênitos da Glicosilação / Inibidores Enzimáticos / Antibióticos Antituberculose Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article