Structure and inhibition of the SARS coronavirus envelope protein ion channel
- PMID: 19593379
- PMCID: PMC2702000
- DOI: 10.1371/journal.ppat.1000511
Structure and inhibition of the SARS coronavirus envelope protein ion channel
Abstract
The envelope (E) protein from coronaviruses is a small polypeptide that contains at least one alpha-helical transmembrane domain. Absence, or inactivation, of E protein results in attenuated viruses, due to alterations in either virion morphology or tropism. Apart from its morphogenetic properties, protein E has been reported to have membrane permeabilizing activity. Further, the drug hexamethylene amiloride (HMA), but not amiloride, inhibited in vitro ion channel activity of some synthetic coronavirus E proteins, and also viral replication. We have previously shown for the coronavirus species responsible for severe acute respiratory syndrome (SARS-CoV) that the transmembrane domain of E protein (ETM) forms pentameric alpha-helical bundles that are likely responsible for the observed channel activity. Herein, using solution NMR in dodecylphosphatidylcholine micelles and energy minimization, we have obtained a model of this channel which features regular alpha-helices that form a pentameric left-handed parallel bundle. The drug HMA was found to bind inside the lumen of the channel, at both the C-terminal and the N-terminal openings, and, in contrast to amiloride, induced additional chemical shifts in ETM. Full length SARS-CoV E displayed channel activity when transiently expressed in human embryonic kidney 293 (HEK-293) cells in a whole-cell patch clamp set-up. This activity was significantly reduced by hexamethylene amiloride (HMA), but not by amiloride. The channel structure presented herein provides a possible rationale for inhibition, and a platform for future structure-based drug design of this potential pharmacological target.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures
Similar articles
-
Coronavirus Proteins as Ion Channels: Current and Potential Research.Front Immunol. 2020 Oct 9;11:573339. doi: 10.3389/fimmu.2020.573339. eCollection 2020. Front Immunol. 2020. PMID: 33154751 Free PMC article. Review.
-
Structural model of the SARS coronavirus E channel in LMPG micelles.Biochim Biophys Acta Biomembr. 2018 Jun;1860(6):1309-1317. doi: 10.1016/j.bbamem.2018.02.017. Epub 2018 Feb 21. Biochim Biophys Acta Biomembr. 2018. PMID: 29474890 Free PMC article.
-
Structural flexibility of the pentameric SARS coronavirus envelope protein ion channel.Biophys J. 2008 Sep 15;95(6):L39-41. doi: 10.1529/biophysj.108.133041. Epub 2008 Jul 25. Biophys J. 2008. PMID: 18658207 Free PMC article.
-
Hexamethylene amiloride blocks E protein ion channels and inhibits coronavirus replication.Virology. 2006 Sep 30;353(2):294-306. doi: 10.1016/j.virol.2006.05.028. Epub 2006 Jul 3. Virology. 2006. PMID: 16815524 Free PMC article.
-
Viral ion channels: molecular modeling and simulation.Bioessays. 1998 Dec;20(12):992-1000. doi: 10.1002/(SICI)1521-1878(199812)20:12<992::AID-BIES5>3.0.CO;2-7. Bioessays. 1998. PMID: 10048299 Review.
Cited by
-
Transmembrane conformation of the envelope protein of an alpha coronavirus, NL63.Protein Sci. 2024 Apr;33(4):e4923. doi: 10.1002/pro.4923. Protein Sci. 2024. PMID: 38501465 Free PMC article.
-
Developing inhibitory peptides against SARS-CoV-2 envelope protein.PLoS Biol. 2024 Mar 14;22(3):e3002522. doi: 10.1371/journal.pbio.3002522. eCollection 2024 Mar. PLoS Biol. 2024. PMID: 38483887 Free PMC article.
-
Membrane Condensation and Curvature Induced by SARS-CoV-2 Envelope Protein.Langmuir. 2024 Feb 6;40(5):2646-2655. doi: 10.1021/acs.langmuir.3c03079. Epub 2024 Jan 22. Langmuir. 2024. PMID: 38258382 Free PMC article.
-
Analysis of SARS-CoV-2 genome evolutionary patterns.Microbiol Spectr. 2024 Feb 6;12(2):e0265423. doi: 10.1128/spectrum.02654-23. Epub 2024 Jan 10. Microbiol Spectr. 2024. PMID: 38197644 Free PMC article.
-
Dimeric Transmembrane Structure of the SARS-CoV-2 E Protein.Commun Biol. 2023 Nov 1;6(1):1109. doi: 10.1038/s42003-023-05490-x. Commun Biol. 2023. PMID: 37914906 Free PMC article.
References
-
- Siddell SG. The Coronaviridae; an introduction. New York: Plenum Press; 1995.
-
- Cavanagh D. Coronavirus avian infectious bronchitis virus. Vet Res. 2007;38:281–297. - PubMed
-
- Enjuanes L, Brian D, Cavanagh D, Holmes K, Lai MMC, et al. Coronaviridae. In: van Regenmortel MHV, Fauquet CM, Bishop DHL, Carsten EB, Estes MK, et al., editors. Virus taxonomy Classification and nomenclature of viruses. San Diego: Academic Press; 2000. pp. 835–849.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases
Miscellaneous