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1.A.65 The Coronavirus Viroporin E Protein (Viroporin E) Family

Viroporins are a growing family of viral proteins able to enhance membrane permeability, promoting virus budding. The viroporin activity of the E protein from murine hepatitis virus (MHV), a member of the coronaviruses, resulted in exit of labeled nucleotides from E. coli cells to the cytoplasm upon expression of MHV E. In addition, enhanced entry of the antibiotic hygromycin B occurred at levels comparable to those observed with the viroporin 6K from Sindbis virus. Mammalian cells are also readily permeabilized by the expression of the MHV E protein. Finally, brefeldin A powerfully blocks the viroporin activity of the E protein in BHK cells, suggesting that an intact vesicular system is necessary for this coronavirus to permeabilize mammalian cells (Madan et al., 2005). The E protein has been described as a cation-selective Ca2+ channel (Harrison et al. 2022). The E channel maintains its multi-ionic non-specific neutral character even in concentrated solutions of Ca2+. In contrast to previous studies, Surya et al. 2023 found no evidence that SARS-CoV-2 E channel activation requires a particular voltage, high calcium concentrations or low pH, in agreement with available data from SARS-CoV-1 E. In addition, sedimentation velocity experiments suggest that the E channel population is mostly pentameric, but very dynamic and probably heterogeneous, consistent with the broad distribution of conductance values typically found in electrophysiological experiments. The latter has been explained by the presence of proteolipidic channel structures (Surya et al. 2023).

More recently, coronavirus (CoV) envelope (E) protein ion channel activity was determined in channels formed in planar lipid bilayers by peptides representing either the transmembrane domain of severe acute respiratory syndrome CoV (SARS-CoV) E protein, or the full-length E protein. Both of them formed voltage-independent ion-conductive pores with symmetric ion transport properties (Verdiá-Báguena et al., 2012). Mutations N15A and V25F located in the transmembrane domain prevented ion conductivity. E protein derived channels showed no cation preference in non-charged lipid membranes, whereas they behaved as pores with mild cation selectivity in negatively-charged lipid membranes. Thus, the ion conductance was controlled by the lipid composition of the membrane. Lipid charge also regulated the selectivity of a HCoV-229E E protein derived peptide. These results suggested that the lipids are functionally involved in E protein ion channel activity, forming a protein-lipid pore (Verdiá-Báguena et al. 2013). Refinement of the e-protein structure in a native-like environment by molecular dynamics simulations has been achieved, and it shows that it induced local membrane curvature while decreasing local lipid order (Yang et al. 2022). The SARS-CoV-2 envelope protein forms clustered pentamers in lipid bilayers (Somberg et al. 2022).

HydroDock can build hydrated drug-target complexes from scratch. The program requires only the dry target and drug structures and produces their complexes with appropriately positioned water molecules. As a test application of the protocol, Zsidó et al. 2021 built the structures of amantadine derivatives in complex with the influenza M2 transmembrane ion channel. The repositioning of amantadine derivatives from this influenza target to the SARS-CoV-2 envelope protein was also investigated. Excellent agreement was observed between experiments and the structures determined by HydroDock. The atomic resolution complex structures showed that water plays a similar role in the binding of amphipathic amantadine derivatives to transmembrane ion channels of both influenza A and SARS-CoV-2. While the hydrophobic regions of the channels capture the bulky hydrocarbon group of the ligand, the surrounding waters direct its orientation parallel with the axes of the channels via bridging interactions with the ionic ligand head (Zsidó et al. 2021).

The generalized reaction catalyzed by the MHV E protein is:

small molecules (out) small molecules (in)

This family belongs to the: Viroporin-3.

References associated with 1.A.65 family:

Breitinger, U., N.K.M. Ali, H. Sticht, and H.G. Breitinger. (2021). Inhibition of SARS CoV Envelope Protein by Flavonoids and Classical Viroporin Inhibitors. Front Microbiol 12: 692423. 34305855
Cabrera-Garcia, D., R. Bekdash, G.W. Abbott, M. Yazawa, and N.L. Harrison. (2021). The envelope protein of SARS-CoV-2 increases intra-Golgi pH and forms a cation channel that is regulated by pH. J. Physiol. 599: 2851-2868. 33709461
Cao, Y., R. Yang, W. Wang, I. Lee, R. Zhang, W. Zhang, J. Sun, B. Xu, and X. Meng. (2020). Computational Study of the Ion and Water Permeation and Transport Mechanisms of the SARS-CoV-2 Pentameric E Protein Channel. Front Mol Biosci 7: 565797. 33173781
Castaño-Rodriguez, C., J.M. Honrubia, J. Gutiérrez-Álvarez, M.L. DeDiego, J.L. Nieto-Torres, J.M. Jimenez-Guardeño, J.A. Regla-Nava, R. Fernandez-Delgado, C. Verdia-Báguena, M. Queralt-Martín, G. Kochan, S. Perlman, V.M. Aguilella, I. Sola, and L. Enjuanes. (2018). Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis. mBio 9:. 29789363
Cheng, F.J., C.Y. Ho, T.S. Li, Y. Chen, Y.L. Yeh, Y.L. Wei, T.K. Huynh, B.R. Chen, H.Y. Ko, C.S. Hsueh, M. Tan, Y.C. Wu, H.C. Huang, C.H. Tang, C.H. Chen, C.Y. Tu, and W.C. Huang. (2023). Umbelliferone and eriodictyol suppress the cellular entry of SARS-CoV-2. Cell Biosci 13: 118. 37381062
Dregni, A.J., M.J. McKay, W. Surya, M. Queralt-Martin, J. Medeiros-Silva, H.K. Wang, V. Aguilella, J. Torres, and M. Hong. (2023). The Cytoplasmic Domain of the SARS-CoV-2 Envelope Protein Assembles into a β-Sheet Bundle in Lipid Bilayers. J. Mol. Biol. 435: 167966. 36682677
Harrison, N.L., G.W. Abbott, M. Gentzsch, A. Aleksandrov, A. Moroni, G. Thiel, S. Grant, C.G. Nichols, H.A. Lester, A. Hartel, K. Shepard, D.C. Garcia, and M. Yazawa. (2022). How many SARS-CoV-2 "viroporins" are really ion channels? Commun Biol 5: 859. 36008538
Henke, W., H. Waisner, S.P. Arachchige, M. Kalamvoki, and E. Stephens. (2022). The Envelope Proteins from SARS-CoV-2 and SARS-CoV Potently Reduce the Infectivity of Human Immunodeficiency Virus type 1 (HIV-1). Res Sq. 36324807
Hong, M., V. Mandala, M. McKay, A. Shcherbakov, A. Dregni, and A. Kolocouris. (2020). Structure and Drug Binding of the SARS-CoV-2 Envelope Protein in Phospholipid Bilayers. Res Sq. 32995764
Jalily, P.H., H. Jalily Hasani, and D. Fedida. (2022). In Silico Evaluation of Hexamethylene Amiloride Derivatives as Potential Luminal Inhibitors of SARS-CoV-2 E Protein. Int J Mol Sci 23:. 36142556
Lu, H., Z. Liu, X. Deng, S. Chen, R. Zhou, R. Zhao, R. Parandaman, A. Thind, J. Henley, L. Tian, J. Yu, L. Comai, P. Feng, and W. Yuan. (2023). Potent NKT cell ligands overcome SARS-CoV-2 immune evasion to mitigate viral pathogenesis in mouse models. PLoS Pathog 19: e1011240. 36961850
Madan, V., J. García Mde, M.A. Sanz, and L. Carrasco. (2005). Viroporin activity of murine hepatitis virus E protein. FEBS Lett. 579(17):3607-3612. 15963987
Mandala, V.S., M.J. McKay, A.A. Shcherbakov, A.J. Dregni, A. Kolocouris, and M. Hong. (2020). Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers. Nat Struct Mol Biol 27: 1202-1208. 33177698
Medeiros-Silva, J., A.J. Dregni, N.H. Somberg, P. Duan, and M. Hong. (2023). Atomic structure of the open SARS-CoV-2 E viroporin. Sci Adv 9: eadi9007. 37831764
Medeiros-Silva, J., N.H. Somberg, H.K. Wang, M.J. McKay, V.S. Mandala, A.J. Dregni, and M. Hong. (2022). pH- and Calcium-Dependent Aromatic Network in the SARS-CoV-2 Envelope Protein. J. Am. Chem. Soc. 144: 6839-6850. 35380805
Nieto-Torres JL., Verdia-Baguena C., Jimenez-Guardeno JM., Regla-Nava JA., Castano-Rodriguez C., Fernandez-Delgado R., Torres J., Aguilella VM. and Enjuanes L. (2015). Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology. 485:330-9. 26331680
Park, S.H., H. Siddiqi, D.V. Castro, A.A. De Angelis, A.L. Oom, C.A. Stoneham, M.K. Lewinski, A.E. Clark, B.A. Croker, A.F. Carlin, J. Guatelli, and S.J. Opella. (2021). Interactions of SARS-CoV-2 envelope protein with amilorides correlate with antiviral activity. PLoS Pathog 17: e1009519. 34003853
Ruch, T.R. and C.E. Machamer. (2012). A single polar residue and distinct membrane topologies impact the function of the infectious bronchitis coronavirus e protein. PLoS Pathog 8: e1002674. 22570613
Scott, C. and S. Griffin. (2015). Viroporins: structure, function and potential as antiviral targets. J Gen Virol 96: 2000-2027. 26023149
Somberg, N.H., J. Medeiros-Silva, H. Jo, J. Wang, W.F. DeGrado, and M. Hong. (2023). Hexamethylene Amiloride Binds the SARS-CoV-2 Envelope Protein at the Protein-Lipid Interface. Protein. Sci. e4755. [Epub: Ahead of Print] 37632140
Somberg, N.H., W.W. Wu, J. Medeiros-Silva, A.J. Dregni, H. Jo, W.F. DeGrado, and M. Hong. (2022). SARS-CoV-2 Envelope Protein Forms Clustered Pentamers in Lipid Bilayers. Biochemistry 61: 2280-2294. 36219675
Surya, W., E. Tavares-Neto, A. Sanchis, M. Queralt-Martín, A. Alcaraz, J. Torres, and V.M. Aguilella. (2023). The Complex Proteolipidic Behavior of the SARS-CoV-2 Envelope Protein Channel: Weak Selectivity and Heterogeneous Oligomerization. Int J Mol Sci 24:. 37569828
Surya, W., Y. Li, C. Verdià-Bàguena, V.M. Aguilella, and J. Torres. (2015). MERS coronavirus envelope protein has a single transmembrane domain that forms pentameric ion channels. Virus Res 201: 61-66. 25733052
Takano T., Nakano K., Doki T. and Hohdatsu T. (2015). Differential effects of viroporin inhibitors against feline infectious peritonitis virus serotypes I and II. Arch Virol. 160(5):1163-70. 25701212
To, J., W. Surya, T.S. Fung, Y. Li, C. Verdià-Bàguena, M. Queralt-Martin, V.M. Aguilella, D.X. Liu, and J. Torres. (2016). Channel inactivating mutations and their revertant mutants in the envelope protein of the infectious bronchitis virus. J. Virol. [Epub: Ahead of Print] 27974570
Torres, J., K. Parthasarathy, X. Lin, R. Saravanan, A. Kukol, and D.X. Liu. (2006). Model of a putative pore: the pentameric α-helical bundle of SARS coronavirus E protein in lipid bilayers. Biophys. J. 91: 938-947. 16698774
Torres, J., U. Maheswari, K. Parthasarathy, L. Ng, D.X. Liu, and X. Gong. (2007). Conductance and amantadine binding of a pore formed by a lysine-flanked transmembrane domain of SARS coronavirus envelope protein. Protein. Sci. 16: 2065-2071. 17766393
Townsend, J.A., O. Fapohunda, Z. Wang, H. Pham, M.T. Taylor, B. Kloss, S.H. Park, S. Opella, C.A. Aspinwall, and M.T. Marty. (2024). Differences in Oligomerization of the SARS-CoV-2 Envelope Protein, Poliovirus VP4, and HIV Vpu. Biochemistry. [Epub: Ahead of Print] 38216552
Verdia-Baguena C., Nieto-Torres JL., Alcaraz A., Dediego ML., Enjuanes L. and Aguilella VM. (2013). Analysis of SARS-CoV E protein ion channel activity by tuning the protein and lipid charge. Biochim Biophys Acta. 1828(9):2026-31. 23688394
Verdiá-Báguena, C., J.L. Nieto-Torres, A. Alcaraz, M.L. Dediego, J. Torres, V.M. Aguilella, and L. Enjuanes. (2012). Coronavirus E protein forms ion channels with functionally and structurally-involved membrane lipids. Virology 432: 485-494. 22832120
Wang, C.W. and W.B. Fischer. (2022). Rotational Dynamics of The Transmembrane Domains Play an Important Role in Peptide Dynamics of Viral Fusion and Ion Channel Forming Proteins-A Molecular Dynamics Simulation Study. Viruses 14:. 35458429
Yadav, R., C. Choudhury, Y. Kumar, and A. Bhatia. (2022). Virtual repurposing of ursodeoxycholate and chenodeoxycholate as lead candidates against SARS-Cov2-Envelope protein: A molecular dynamics investigation. J Biomol Struct Dyn 40: 5147-5158. 33382021
Yang, R., S. Wu, S. Wang, G. Rubino, J.D. Nickels, and X. Cheng. (2022). Refinement of SARS-CoV-2 envelope protein structure in a native-like environment by molecular dynamics simulations. Front Mol Biosci 9: 1027223. 36299297
Zhang, R., H. Qin, R. Prasad, R. Fu, H.X. Zhou, and T.A. Cross. (2023). Dimeric Transmembrane Structure of the SARS-CoV-2 E Protein. bioRxiv. 37214926
Zsidó, B.Z., R. Börzsei, V. Szél, and C. Hetényi. (2021). Determination of Ligand Binding Modes in Hydrated Viral Ion Channels to Foster Drug Design and Repositioning. J Chem Inf Model 61: 4011-4022. 34313421