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  1. Article ; Online: The trajectory of intrahelical lesion recognition and extrusion by the human 8-oxoguanine DNA glycosylase.

    Shigdel, Uddhav K / Ovchinnikov, Victor / Lee, Seung-Joo / Shih, Jenny A / Karplus, Martin / Nam, Kwangho / Verdine, Gregory L

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 4437

    Abstract: Efficient search for DNA damage embedded in vast expanses of the DNA genome presents one of the greatest challenges to DNA repair enzymes. We report here crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase, hOGG1, that interact with the DNA ... ...

    Abstract Efficient search for DNA damage embedded in vast expanses of the DNA genome presents one of the greatest challenges to DNA repair enzymes. We report here crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase, hOGG1, that interact with the DNA containing the damaged base oxoG and the normal base G while they are nested in the DNA helical stack. The structures reveal that hOGG1 engages the DNA using different protein-DNA contacts from those observed in the previously determined lesion recognition complex and other hOGG1-DNA complexes. By applying molecular dynamics simulations, we have determined the pathways taken by the lesion and normal bases when extruded from the DNA helix and their associated free energy profiles. These results reveal how the human oxoG DNA glycosylase hOGG1 locates the lesions inside the DNA helix and facilitates their extrusion for repair.
    MeSH term(s) Crystallography, X-Ray ; DNA/chemistry ; DNA Damage ; DNA Glycosylases/chemistry ; DNA Repair ; Molecular Dynamics Simulation ; Protein Conformation
    Chemical Substances DNA (9007-49-2) ; DNA Glycosylases (EC 3.2.2.-) ; oxoguanine glycosylase 1, human (EC 3.2.2.-)
    Language English
    Publishing date 2020-09-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-18290-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The trajectory of intrahelical lesion recognition and extrusion by the human 8-oxoguanine DNA glycosylase

    Uddhav K. Shigdel / Victor Ovchinnikov / Seung-Joo Lee / Jenny A. Shih / Martin Karplus / Kwangho Nam / Gregory L. Verdine

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 8

    Abstract: DNA glycosylases are lesion-specific enzymes that recognize specific nucleobase damages and catalyze their excision through cleavage of the glycosidic bond. Here, the authors present the crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase ... ...

    Abstract DNA glycosylases are lesion-specific enzymes that recognize specific nucleobase damages and catalyze their excision through cleavage of the glycosidic bond. Here, the authors present the crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase bound to undamaged DNA and to DNA containing an intrahelical oxoG lesion and further analyse these structures with molecular dynamics simulations, which allows them to characterise the base-extrusion pathways.
    Keywords Science ; Q
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: The trajectory of intrahelical lesion recognition and extrusion by the human 8-oxoguanine DNA glycosylase

    Uddhav K. Shigdel / Victor Ovchinnikov / Seung-Joo Lee / Jenny A. Shih / Martin Karplus / Kwangho Nam / Gregory L. Verdine

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 8

    Abstract: DNA glycosylases are lesion-specific enzymes that recognize specific nucleobase damages and catalyze their excision through cleavage of the glycosidic bond. Here, the authors present the crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase ... ...

    Abstract DNA glycosylases are lesion-specific enzymes that recognize specific nucleobase damages and catalyze their excision through cleavage of the glycosidic bond. Here, the authors present the crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase bound to undamaged DNA and to DNA containing an intrahelical oxoG lesion and further analyse these structures with molecular dynamics simulations, which allows them to characterise the base-extrusion pathways.
    Keywords Science ; Q
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface.

    Shigdel, Uddhav K / Lee, Seung-Joo / Sowa, Mathew E / Bowman, Brian R / Robison, Keith / Zhou, Minyun / Pua, Khian Hong / Stiles, Dylan T / Blodgett, Joshua A V / Udwary, Daniel W / Rajczewski, Andrew T / Mann, Alan S / Mostafavi, Siavash / Hardy, Tara / Arya, Sukrat / Weng, Zhigang / Stewart, Michelle / Kenyon, Kyle / Morgenstern, Jay P /
    Pan, Ende / Gray, Daniel C / Pollock, Roy M / Fry, Andrew M / Klausner, Richard D / Townson, Sharon A / Verdine, Gregory L

    Proceedings of the National Academy of Sciences of the United States of America

    2020  Volume 117, Issue 29, Page(s) 17195–17203

    Abstract: The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural ... ...

    Abstract The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.
    MeSH term(s) Actinobacteria/genetics ; Actinobacteria/metabolism ; Amino Acid Sequence ; Antiviral Agents/chemistry ; Antiviral Agents/metabolism ; Antiviral Agents/pharmacology ; Autoantigens/genetics ; Autoantigens/metabolism ; Calcineurin/genetics ; Calcineurin/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Evolution, Molecular ; Genome, Bacterial ; HEK293 Cells ; Humans ; Macrolides/chemistry ; Macrolides/metabolism ; Macrolides/pharmacology ; Models, Molecular ; Protein Conformation ; Protein Interaction Domains and Motifs/drug effects ; Sequence Homology ; Sirolimus/chemistry ; Sirolimus/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/metabolism ; Small Molecule Libraries/pharmacology ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; Tacrolimus Binding Protein 1A/chemistry ; Tacrolimus Binding Protein 1A/metabolism
    Chemical Substances Antiviral Agents ; Autoantigens ; Cell Cycle Proteins ; CEP250 protein, human ; Macrolides ; Small Molecule Libraries ; WDB002 ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Calcineurin (EC 3.1.3.16) ; Tacrolimus Binding Protein 1A (EC 5.2.1.-) ; Sirolimus (W36ZG6FT64)
    Keywords covid19
    Language English
    Publishing date 2020-06-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2006560117
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface

    Shigdel, Uddhav K / Lee, Seung-Joo / Sowa, Mathew E / Bowman, Brian R / Robison, Keith / Zhou, Minyun / Pua, Khian Hong / Stiles, Dylan T / Blodgett, Joshua A V / Udwary, Daniel W / Rajczewski, Andrew T / Mann, Alan S / Mostafavi, Siavash / Hardy, Tara / Arya, Sukrat / Weng, Zhigang / Stewart, Michelle / Kenyon, Kyle / Morgenstern, Jay P /
    Pan, Ende / Gray, Daniel C / Pollock, Roy M / Fry, Andrew M / Klausner, Richard D / Townson, Sharon A / Verdine, Gregory L

    Proc Natl Acad Sci U S A

    Abstract: The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural ... ...

    Abstract The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #624792
    Database COVID19

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  6. Article ; Online: Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface.

    Shigdel, Uddhav K / Lee, Seung-Joo / Sowa, Mathew E / Bowman, Brian R / Robison, Keith / Zhou, Minyun / Pua, Khian Hong / Stiles, Dylan T / Blodgett, Joshua AV / Udwary, Daniel W / Rajczewski, Andrew T / Mann, Alan S / Mostafavi, Siavash / Hardy, Tara / Arya, Sukrat / Weng, Zhigang / Stewart, Michelle / Kenyon, Kyle / Morgenstern, Jay P /
    Pan, Ende / Gray, Daniel C / Pollock, Roy M / Fry, Andrew M / Klausner, Richard D / Townson, Sharon A / Verdine, Gregory L

    Proceedings of the National Academy of Sciences of the United States of America, vol 117, iss 29

    2020  

    Abstract: The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural ... ...

    Abstract The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.
    Keywords Humans ; Actinobacteria ; Sirolimus ; Calcineurin ; Tacrolimus Binding Protein 1A ; Cell Cycle Proteins ; Autoantigens ; Anti-Bacterial Agents ; Evolution ; Molecular ; Amino Acid Sequence ; Protein Conformation ; Sequence Homology ; Genome ; Bacterial ; Models ; Protein Interaction Domains and Motifs ; Small Molecule Libraries ; HEK293 Cells ; TOR Serine-Threonine Kinases ; FK506-binding protein ; genome mining ; natural products ; covid19
    Subject code 612
    Publishing date 2020-07-01
    Publisher eScholarship, University of California
    Publishing country us
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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