Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers
An essential protein of the SARS-CoV-2 virus, the envelope protein E, forms a homopentameric cation channel that is important for virus pathogenicity. Here we report a 2.1-Å structure and the drug-binding site of E’s transmembrane domain (ETM), determined using solid-state NMR spectroscopy. In lipid...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2022
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| Online Access: | https://hdl.handle.net/1721.1/141070 |
| _version_ | 1826202191237480448 |
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| author | Mandala, Venkata S McKay, Matthew J Shcherbakov, Alexander A Dregni, Aurelio J Kolocouris, Antonios Hong, Mei |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Mandala, Venkata S McKay, Matthew J Shcherbakov, Alexander A Dregni, Aurelio J Kolocouris, Antonios Hong, Mei |
| author_sort | Mandala, Venkata S |
| collection | MIT |
| description | An essential protein of the SARS-CoV-2 virus, the envelope protein E, forms a homopentameric cation channel that is important for virus pathogenicity. Here we report a 2.1-Å structure and the drug-binding site of E’s transmembrane domain (ETM), determined using solid-state NMR spectroscopy. In lipid bilayers that mimic the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) membrane, ETM forms a five-helix bundle surrounding a narrow pore. The protein deviates from the ideal α-helical geometry due to three phenylalanine residues, which stack within each helix and between helices. Together with valine and leucine interdigitation, these cause a dehydrated pore compared with the viroporins of influenza viruses and HIV. Hexamethylene amiloride binds the polar amino-terminal lumen, whereas acidic pH affects the carboxy-terminal conformation. Thus, the N- and C-terminal halves of this bipartite channel may interact with other viral and host proteins semi-independently. The structure sets the stage for designing E inhibitors as antiviral drugs. |
| first_indexed | 2024-09-23T12:03:38Z |
| format | Article |
| id | mit-1721.1/141070 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:03:38Z |
| publishDate | 2022 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1410702023-06-22T18:53:45Z Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers Mandala, Venkata S McKay, Matthew J Shcherbakov, Alexander A Dregni, Aurelio J Kolocouris, Antonios Hong, Mei Massachusetts Institute of Technology. Department of Chemistry An essential protein of the SARS-CoV-2 virus, the envelope protein E, forms a homopentameric cation channel that is important for virus pathogenicity. Here we report a 2.1-Å structure and the drug-binding site of E’s transmembrane domain (ETM), determined using solid-state NMR spectroscopy. In lipid bilayers that mimic the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) membrane, ETM forms a five-helix bundle surrounding a narrow pore. The protein deviates from the ideal α-helical geometry due to three phenylalanine residues, which stack within each helix and between helices. Together with valine and leucine interdigitation, these cause a dehydrated pore compared with the viroporins of influenza viruses and HIV. Hexamethylene amiloride binds the polar amino-terminal lumen, whereas acidic pH affects the carboxy-terminal conformation. Thus, the N- and C-terminal halves of this bipartite channel may interact with other viral and host proteins semi-independently. The structure sets the stage for designing E inhibitors as antiviral drugs. 2022-03-08T20:31:03Z 2022-03-08T20:31:03Z 2020 2022-03-08T20:28:07Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/141070 Mandala, Venkata S, McKay, Matthew J, Shcherbakov, Alexander A, Dregni, Aurelio J, Kolocouris, Antonios et al. 2020. "Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers." Nature Structural and Molecular Biology, 27 (12). en 10.1038/S41594-020-00536-8 Nature Structural and Molecular Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Mandala, Venkata S McKay, Matthew J Shcherbakov, Alexander A Dregni, Aurelio J Kolocouris, Antonios Hong, Mei Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers |
| title | Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers |
| title_full | Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers |
| title_fullStr | Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers |
| title_full_unstemmed | Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers |
| title_short | Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers |
| title_sort | structure and drug binding of the sars cov 2 envelope protein transmembrane domain in lipid bilayers |
| url | https://hdl.handle.net/1721.1/141070 |
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