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Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase

Flaviviruses use a ~70 nucleotide stem-loop structure called stem-loop A (SLA) at the 5′ end of the RNA genome as a promoter for RNA synthesis. Flaviviral polymerase NS5 specifically recognizes SLA to initiate RNA synthesis and methylate the 5′ guanosine cap. We report the crystal structures of deng...

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Autores principales: Lee, Eunhye, Bujalowski, Paul J., Teramoto, Tadahisa, Gottipati, Keerthi, Scott, Seth D., Padmanabhan, Radhakrishnan, Choi, Kyung H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100141/
https://www.ncbi.nlm.nih.gov/pubmed/33953197
http://dx.doi.org/10.1038/s41467-021-22846-1
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author Lee, Eunhye
Bujalowski, Paul J.
Teramoto, Tadahisa
Gottipati, Keerthi
Scott, Seth D.
Padmanabhan, Radhakrishnan
Choi, Kyung H.
author_facet Lee, Eunhye
Bujalowski, Paul J.
Teramoto, Tadahisa
Gottipati, Keerthi
Scott, Seth D.
Padmanabhan, Radhakrishnan
Choi, Kyung H.
author_sort Lee, Eunhye
collection PubMed
description Flaviviruses use a ~70 nucleotide stem-loop structure called stem-loop A (SLA) at the 5′ end of the RNA genome as a promoter for RNA synthesis. Flaviviral polymerase NS5 specifically recognizes SLA to initiate RNA synthesis and methylate the 5′ guanosine cap. We report the crystal structures of dengue (DENV) and Zika virus (ZIKV) SLAs. DENV and ZIKV SLAs differ in the relative orientations of their top stem-loop helices to bottom stems, but both form an intermolecular three-way junction with a neighboring SLA molecule. To understand how NS5 engages SLA, we determined the SLA-binding site on NS5 and modeled the NS5-SLA complex of DENV and ZIKV. Our results show that the gross conformational differences seen in DENV and ZIKV SLAs can be compensated by the differences in the domain arrangements in DENV and ZIKV NS5s. We describe two binding modes of SLA and NS5 and propose an SLA-mediated RNA synthesis mechanism.
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spelling pubmed-81001412021-05-11 Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase Lee, Eunhye Bujalowski, Paul J. Teramoto, Tadahisa Gottipati, Keerthi Scott, Seth D. Padmanabhan, Radhakrishnan Choi, Kyung H. Nat Commun Article Flaviviruses use a ~70 nucleotide stem-loop structure called stem-loop A (SLA) at the 5′ end of the RNA genome as a promoter for RNA synthesis. Flaviviral polymerase NS5 specifically recognizes SLA to initiate RNA synthesis and methylate the 5′ guanosine cap. We report the crystal structures of dengue (DENV) and Zika virus (ZIKV) SLAs. DENV and ZIKV SLAs differ in the relative orientations of their top stem-loop helices to bottom stems, but both form an intermolecular three-way junction with a neighboring SLA molecule. To understand how NS5 engages SLA, we determined the SLA-binding site on NS5 and modeled the NS5-SLA complex of DENV and ZIKV. Our results show that the gross conformational differences seen in DENV and ZIKV SLAs can be compensated by the differences in the domain arrangements in DENV and ZIKV NS5s. We describe two binding modes of SLA and NS5 and propose an SLA-mediated RNA synthesis mechanism. Nature Publishing Group UK 2021-05-05 /pmc/articles/PMC8100141/ /pubmed/33953197 http://dx.doi.org/10.1038/s41467-021-22846-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lee, Eunhye
Bujalowski, Paul J.
Teramoto, Tadahisa
Gottipati, Keerthi
Scott, Seth D.
Padmanabhan, Radhakrishnan
Choi, Kyung H.
Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase
title Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase
title_full Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase
title_fullStr Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase
title_full_unstemmed Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase
title_short Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase
title_sort structures of flavivirus rna promoters suggest two binding modes with ns5 polymerase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100141/
https://www.ncbi.nlm.nih.gov/pubmed/33953197
http://dx.doi.org/10.1038/s41467-021-22846-1
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