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4. i-Motif folding intermediates with zero-nucleotide loops are trapped by 2'-fluoroarabinocytidine via F···H and O···H hydrogen bonds

Author

Ministerio de Ciencia e Innovación (España), European Commission, Generalitat de Catalunya, Natural Sciences and Engineering Research Council of Canada, Fonds de Recherche du Québec, El-Khoury, Roberto [0000-0002-8068-4566], González, Carlos [0000-0001-8796-1282], Garavís, Miguel [0000-0003-1889-1713], Damha, Masad J. [0000-0002-4458-1623], El-Khoury, Roberto, Macaluso, Veronica, Hennecker, Christopher, Mittermaier, Anthony K., Orozco, Modesto, González, Carlos, Garavís, Miguel, Damha, Masad J., Ministerio de Ciencia e Innovación (España), European Commission, Generalitat de Catalunya, Natural Sciences and Engineering Research Council of Canada, Fonds de Recherche du Québec, El-Khoury, Roberto [0000-0002-8068-4566], González, Carlos [0000-0001-8796-1282], Garavís, Miguel [0000-0003-1889-1713], Damha, Masad J. [0000-0002-4458-1623], El-Khoury, Roberto, Macaluso, Veronica, Hennecker, Christopher, Mittermaier, Anthony K., Orozco, Modesto, González, Carlos, Garavís, Miguel, and Damha, Masad J.

Abstract

G-quadruplex and i-motif nucleic acid structures are believed to fold through kinetic partitioning mechanisms. Such mechanisms explain the structural heterogeneity of G-quadruplex metastable intermediates which have been extensively reported. On the other hand, i-motif folding is regarded as predictable, and research on alternative i-motif folds is limited. While TC5 normally folds into a stable tetrameric i-motif in solution, we report that 2'-deoxy-2'-fluoroarabinocytidine (araF-C) substitutions can prompt TC5 to form an off-pathway and kinetically-trapped dimeric i-motif, thereby expanding the scope of i-motif folding landscapes. This i-motif is formed by two strands, associated head-to-head, and featuring zero-nucleotide loops which have not been previously observed. Through spectroscopic and computational analyses, we also establish that the dimeric i-motif is stabilized by fluorine and non-fluorine hydrogen bonds, thereby explaining the superlative stability of araF-C modified i-motifs. Comparative experimental findings suggest that the strength of these interactions depends on the flexible sugar pucker adopted by the araF-C residue. Overall, the findings reported here provide a new role for i-motifs in nanotechnology and also pose the question of whether unprecedented i-motif folds may exist in vivo.

Published
2023

5. A naturally occurring G11S mutation in the 3C‐like protease from the SARS‐CoV‐2 virus dramatically weakens the dimer interface.

Author

Wang, Guanyu, Venegas, Felipe A., Rueda, Andres M., Weerasinghe, Nuwani W., Uggowitzer, Kevin A., Thibodeaux, Christopher J., Moitessier, Nicolas, and Mittermaier, Anthony K.

Abstract

The 3C‐like protease (3CLpro) is crucial to the replication of SARS‐CoV‐2, the causative agent of COVID‐19, and is the target of several successful drugs including Paxlovid and Xocova. Nevertheless, the emergence of viral resistance underlines the need for alternative drug strategies. 3CLpro only functions as a homodimer, making the protein–protein interface an attractive drug target. Dimerization is partly mediated by a conserved glycine at position 11. However, some naturally occurring SARS‐CoV‐2 sequences contain a serine at this position, potentially disrupting the dimer. We have used concentration‐dependent activity assays and mass spectrometry to show that indeed the G11S mutation reduces the stability of the dimer by 600‐fold. This helps to set a quantitative benchmark for the minimum potency required of any future protein–protein interaction inhibitors targeting 3CLpro and raises interesting questions regarding how coronaviruses bearing such weakly dimerizing 3CLpro enzymes are capable of replication. [ABSTRACT FROM AUTHOR]

Published
2024
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20. A naturally occurring G11S mutation in the 3C-like protease from the SARS-CoV-2 virus dramatically weakens the dimer interface.

Author

Wang G, Venegas FA, Rueda AM, Weerasinghe NW, Uggowitzer KA, Thibodeaux CJ, Moitessier N, and Mittermaier AK

Subjects
Humans, Peptide Hydrolases genetics, Cysteine Endopeptidases chemistry, Cysteine Endopeptidases genetics, Mutation, Antiviral Agents chemistry, SARS-CoV-2 genetics, COVID-19
Abstract

The 3C-like protease (3CL pro ) is crucial to the replication of SARS-CoV-2, the causative agent of COVID-19, and is the target of several successful drugs including Paxlovid and Xocova. Nevertheless, the emergence of viral resistance underlines the need for alternative drug strategies. 3CL pro only functions as a homodimer, making the protein-protein interface an attractive drug target. Dimerization is partly mediated by a conserved glycine at position 11. However, some naturally occurring SARS-CoV-2 sequences contain a serine at this position, potentially disrupting the dimer. We have used concentration-dependent activity assays and mass spectrometry to show that indeed the G11S mutation reduces the stability of the dimer by 600-fold. This helps to set a quantitative benchmark for the minimum potency required of any future protein-protein interaction inhibitors targeting 3CL pro and raises interesting questions regarding how coronaviruses bearing such weakly dimerizing 3CL pro enzymes are capable of replication., (© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Published
2024
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