Simultaneous Measurement of Glucose-6-phosphate 3-Dehydrogenase (NtdC) Catalysis and the Nonenzymatic Reaction of Its Product: Kinetics and Isotope Effects on the First Step in Kanosamine Biosynthesis

March 29th, 2017 by Natasha D. Vetter and David R. J. Palmer

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Biochemistry
DOI: 10.1021/acs.biochem.7b00079

Structural and functional insight into human O-GlcNAcase

March 27th, 2017 by Christian Roth

Nature Chemical Biology 13, 610 (2017). doi:10.1038/nchembio.2358

Authors: Christian Roth, Sherry Chan, Wendy A Offen, Glyn R Hemsworth, Lianne I Willems, Dustin T King, Vimal Varghese, Robert Britton, David J Vocadlo & Gideon J Davies

O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value.

Near-infrared optogenetic pair for protein regulation and spectral multiplexing

March 27th, 2017 by Taras A Redchuk

Nature Chemical Biology 13, 633 (2017). doi:10.1038/nchembio.2343

Authors: Taras A Redchuk, Evgeniya S Omelina, Konstantin G Chernov & Vladislav V Verkhusha

  • Posted in Nat Chem Biol, Publications
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Chemical screening identifies ATM as a target for alleviating senescence

March 27th, 2017 by Hyun Tae Kang

Nature Chemical Biology 13, 616 (2017). doi:10.1038/nchembio.2342

Authors: Hyun Tae Kang, Joon Tae Park, Kobong Choi, Yongsub Kim, Hyo Jei Claudia Choi, Chul Won Jung, Young-Sam Lee & Sang Chul Park

  • Posted in Nat Chem Biol, Publications
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Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase

March 27th, 2017 by Stephanie M Stanford

Nature Chemical Biology 13, 624 (2017). doi:10.1038/nchembio.2344

Authors: Stephanie M Stanford, Alexander E Aleshin, Vida Zhang, Robert J Ardecky, Michael P Hedrick, Jiwen Zou, Santhi R Ganji, Matthew R Bliss, Fusayo Yamamoto, Andrey A Bobkov, Janna Kiselar, Yingge Liu, Gregory W Cadwell, Shilpi Khare, Jinghua Yu, Antonio Barquilla, Thomas D Y Chung, Tomas Mustelin, Simon Schenk, Laurie A Bankston, Robert C Liddington, Anthony B Pinkerton & Nunzio Bottini

  • Posted in Nat Chem Biol, Publications
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Insights into activity and inhibition from the crystal structure of human O-GlcNAcase

March 27th, 2017 by Nathaniel L Elsen

Nature Chemical Biology 13, 613 (2017). doi:10.1038/nchembio.2357

Authors: Nathaniel L Elsen, Sangita B Patel, Rachael E Ford, Dawn L Hall, Fred Hess, Hari Kandula, Maria Kornienko, John Reid, Harold Selnick, Jennifer M Shipman, Sujata Sharma, Kevin J Lumb, Stephen M Soisson & Daniel J Klein

O-GlcNAc hydrolase (OGA) catalyzes removal of βα-linked N-acetyl-D-glucosamine from serine and threonine residues. We report crystal structures of Homo sapiens OGA catalytic domain in apo and inhibited states, revealing a flexible dimer that displays three unique conformations and is characterized by subdomain α-helix swapping. These results identify new structural features of the substrate-binding groove adjacent to the catalytic site and open new opportunities for structural, mechanistic and drug discovery activities.

  • Posted in Nat Chem Biol, Publications
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pH regulation in early endosomes and interferon-inducible transmembrane proteins control avian retrovirus fusion [Membrane Biology]

March 24th, 2017 by Tanay M Desai, Mariana Marin, Caleb Mason, Gregory B Melikyan

Enveloped viruses infect host cells by fusing their membranes with those of the host cell, a process mediated by viral glycoproteins upon binding to cognate host receptors or entering into acidic intracellular compartments. Whereas the effect of receptor density on viral infection has been well studied, the role of cell type-specific factors/processes, such as pH regulation, has not been characterized in sufficient detail. Here, we examined the effects of cell-extrinsic factors (buffer environment) and cell-intrinsic factors (interferon-inducible transmembrane proteins, IFITMs), on the pH regulation in early endosomes and on the efficiency of acid-dependent fusion of the Avian Sarcoma and Leukosis Virus, ASLV, with endosomes. First, we found that a modest elevation of external pH can raise the pH in early endosomes in a cell type-dependent manner and thereby delay the acid-induced fusion of endocytosed ASLV. Second, we observed a cell type-dependent delay between the low pH-dependent and temperature-dependent steps of viral fusion, consistent with the delayed enlargement of the fusion pore. Third, ectopic expression of IFITMs, known to potently block influenza virus fusion with late compartments, was found to only partially inhibit ASLV fusion with early endosomes. Interestingly, IFITM expression promoted virus uptake and the acidification of endosomal compartments, resulting in an accelerated fusion rate, when driven by the glycosylphosphatidylinositol-anchored, but not by the transmembrane isoform of the ASLV receptor. Collectively, these results highlight the role of cell-extrinsic and cell-intrinsic factors in regulating the efficiency and kinetics of virus entry and fusion with target cells.

Selective Downregulation of JAK2 and JAK3 by an ATP-Competitive pan-JAK Inhibitor

March 22nd, 2017 by S. Denise Field, Jacob Arkin, Jing Li and Lyn H. Jones

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ACS Chemical Biology
DOI: 10.1021/acschembio.7b00116

Simultaneous quantification of protein order and disorder

March 22nd, 2017 by Pietro Sormanni

Nature Chemical Biology 13, 339 (2017). doi:10.1038/nchembio.2331

Authors: Pietro Sormanni, Damiano Piovesan, Gabriella T Heller, Massimiliano Bonomi, Predrag Kukic, Carlo Camilloni, Monika Fuxreiter, Zsuzsanna Dosztanyi, Rohit V Pappu, M Madan Babu, Sonia Longhi, Peter Tompa, A Keith Dunker, Vladimir N Uversky, Silvio C E Tosatto & Michele Vendruscolo

Nuclear magnetic resonance spectroscopy is transforming our views of proteins by revealing how their structures and dynamics are closely intertwined to underlie their functions and interactions. Compelling representations of proteins as statistical ensembles are uncovering the presence and biological relevance of conformationally heterogeneous states, thus gradually making it possible to go beyond the dichotomy between order and disorder through more quantitative descriptions that span the continuum between them.

Protein folding: Illuminating chaperone activity

March 22nd, 2017 by Danny M Hatters

Nature Chemical Biology 13, 346 (2017). doi:10.1038/nchembio.2332

Author: Danny M Hatters

Pharmacological chaperones are small drugs that stabilize a protein's fold and are being developed to treat diseases arising from protein misfolding. A mathematical framework to model their activity in cells enables insight into their mechanism and capacity to rescue protein foldedness.