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Research Article

Structure and dynamics of whole-sequence homology model of ORF3a protein of SARS-CoV-2: An insight from microsecond molecular dynamics simulations

, , ORCID Icon, , , ORCID Icon & ORCID Icon show all
Received 22 Sep 2022, Accepted 08 Jul 2023, Published online: 01 Aug 2023

References

  • Abbasian, M. H., Mahdavi, B., Mahmanzar, M., Tokhanbigli, S., Mollapour Sisakht, M., Moradi, B., Rahimian, K., & Najmabadi, H. (2022). Analysis of whole-genome sequencing of SARS-CoV-2 reveals recurrent mutations among Iranian patients. MedRxiv, 2022.06.20.22276625. http://medrxiv.org/content/early/2022/06/22/2022.06.20.22276625.abstract
  • Abrams, C. F., & Vanden-Eijnden, E. (2010). Large-scale conformational sampling of proteins using temperature-accelerated molecular dynamics. Proceedings of the National Academy of Sciences of the United States of America, 107(11), 4961–4966. https://doi.org/10.1073/pnas.0914540107
  • Ahmed, S., Mahtarin, R., Ahmed, S. S., Akter, S., Islam, M. S., Mamun, A. A., Islam, R., Hossain, M. N., Ali, M. A., Sultana, M. U. C., Parves, M. R., Ullah, M. O., & Halim, M. A. (2021). Investigating the binding affinity, interaction, and structure-activity-relationship of 76 prescription antiviral drugs targeting RdRp and Mpro of SARS-CoV-2. Journal of Biomolecular Structure & Dynamics, 39(16), 6290–6305. https://doi.org/10.1080/07391102.2020.1796804
  • Aier, I., Varadwaj, P. K., & Raj, U. (2016). Structural insights into conformational stability of both wild-type and mutant EZH2 receptor. Scientific Reports, 6(September), 34984. https://doi.org/10.1038/srep34984
  • Akbarzadeh-Khiavi, M., Torabi, M., Rahbarnia, L., & Safary, A. (2022). Baricitinib combination therapy: A narrative review of repurposed Janus kinase inhibitor against severe SARS-CoV-2 infection. Infection, 50(2), 295–308. https://doi.org/10.1007/s15010-021-01730-6
  • Åkerström, S., Tan, Y. J., & Mirazimi, A. (2006). Amino acids 15-28 in the ectodomain of SARS coronavirus 3a protein induces neutralizing antibodies. FEBS Letters, 580(16), 3799–3803. https://doi.org/10.1016/j.febslet.2006.06.002
  • Arifuzzaman, M., Hamza, A., Zannat, S. S., Fahad, R., Rahman, A., Hosen, S. M. Z., Dash, R., & Hossain, M. K. (2020). Targeting galectin-3 by natural glycosides: A computational approach. Network Modeling Analysis in Health Informatics and Bioinformatics, 9(1), 14. https://doi.org/10.1007/s13721-020-0219-z
  • Benkert, P., Künzli, M., & Schwede, T. (2009). QMEAN server for protein model quality estimation. Nucleic Acids Research, 37(Web Server issue), W510–W514. https://doi.org/10.1093/nar/gkp322
  • Bös, F., & Pleiss, J. (2009). Multiple molecular dynamics simulations of TEM β-lactamase: Dynamics and water binding of the Ω-loop. Biophysical Journal, 97(9), 2550–2558. https://doi.org/10.1016/j.bpj.2009.08.031
  • Bowers, K. J., Chow, E., Xu, H., Dror, R. O., Eastwood, M. P., Gregersen, B. A., Klepeis, J. L., Kolossvary, I., Moraes, M. A., Sacerdoti, F. D., Salmon, J. K., Shan, Y., & Shaw, D. E. (2006). Scalable algorithms for molecular dynamics simulations on commodity clusters [Paper presentation]. SC ‘‘06: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing, Tampa, FL.
  • Cai, H., Chen, Y., Feng, Y., Asadi, M., Kaufman, L., Lee, K., Kehrer, T., Miorin, L., Garcia-Sastre, A., Gusella, G. L., Gu, L., Ni, Z., Mou, S., He, J. C., & Zhou, W. (2023). SARS-CoV-2 viral protein ORF3A injures renal tubules by interacting with TRIM59 to induce STAT3 activation. Molecular Therapy, 31(3), 774–787. https://doi.org/10.1016/j.ymthe.2022.12.008
  • Castaño-Rodriguez, C., Honrubia, J. M., Gutiérrez-Álvarez, J., DeDiego, M. L., Nieto-Torres, J. L., Jimenez-Guardeño, J. M., Regla-Nava, J. A., Fernandez-Delgado, R., Verdia-Báguena, C., Queralt-Martín, M., Kochan, G., Perlman, S., Aguilella, V. M., Sola, I., & Enjuanes, L. (2018). Role of severe acute respiratory syndrome coronavirus viroporins E, 3a, and 8a in replication and pathogenesis. mBio, 9(3), e02325-17. https://doi.org/10.1128/mBio.02325-17
  • Chen, J., Zhang, S., Wang, W., Sun, H., Zhang, Q., & Liu, X. (2021). Binding of inhibitors to BACE1 affected by pH-dependent protonation: An exploration from multiple replica Gaussian accelerated molecular dynamics and MM-GBSA calculations. ACS Chemical Neuroscience, 12(14), 2591–2607. https://doi.org/10.1021/acschemneuro.0c00813
  • Choudhary, M. I., Shaikh, M., Tul-Wahab, A., & Ur-Rahman, A. (2020). In silico identification of potential inhibitors of key SARS-CoV-2 3CL hydrolase (Mpro) via molecular docking, MMGBSA predictive binding energy calculations, and molecular dynamics simulation. PLoS One, 15(7), e0235030. https://doi.org/10.1371/JOURNAL.PONE.0235030
  • Collins, L. T., Elkholy, T., Mubin, S., Hill, D., Williams, R., Ezike, K., & Singhal, A. (2021). Elucidation of SARS-Cov-2 budding mechanisms through molecular dynamics simulations of M and E protein complexes. The Journal of Physical Chemistry Letters, 12(51), 12249–12255. https://doi.org/10.1021/acs.jpclett.1c02955
  • Colovos, C., & Yeates, T. O. (1993). Verification of protein structures: Patterns of nonbonded atomic interactions. Protein Science, 2(9), 1511–1519. https://doi.org/10.1002/pro.5560020916
  • Daddam, J. R., Sreenivasulu, B., Peddanna, K., & Umamahesh, K. (2020). Designing, docking and molecular dynamics simulation studies of novel cloperastine analogues as anti-allergic agents: Homology modeling and active site prediction for the human histamine H1 receptor. RSC Advances, 10(8), 4745–4754. https://doi.org/10.1039/c9ra09245e
  • Djinovic-Carugo, K., & Carugo, O. (2015). Missing strings of residues in protein crystal structures. Intrinsically Disordered Proteins, 3(1), e1095697. https://doi.org/10.1080/21690707.2015.1095697
  • Duran, T., Minatovicz, B., Bai, J., Shin, D., Mohammadiarani, H., & Chaudhuri, B. (2021). Molecular dynamics simulation to uncover the mechanisms of protein instability during freezing. Journal of Pharmaceutical Sciences, 110(6), 2457–2471. https://doi.org/10.1016/j.xphs.2021.01.002
  • Efaz, F. M., Islam, S., Talukder, S. A., Akter, S., Tashrif, M. Z., Ali, M. A., Sufian, M. A., Parves, M. R., Islam, M. J., & Halim, M. A. (2021). Repurposing fusion inhibitor peptide against SARS-CoV-2. Journal of Computational Chemistry, 42(32), 2283–2293. https://doi.org/10.1002/jcc.26758
  • Fallon, L., Belfon, K. A. A., Raguette, L., Wang, Y., Stepanenko, D., Cuomo, A., Guerra, J., Budhan, S., Varghese, S., Corbo, C. P., Rizzo, R. C., & Simmerling, C. (2021). Free energy landscapes from SARS-CoV-2 spike glycoprotein simulations suggest that RBD opening can be modulated via interactions in an allosteric pocket. Journal of the American Chemical Society, 143(30), 11349–11360. https://doi.org/10.1021/jacs.1c00556
  • Frisch, M. J, Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R. & Fox, D. J. (2016). Gaussian 09, revision A.02. Gaussian Inc.
  • Gross, M. (2011). Anarchy in the proteome. Chemistry World, 8(8), 42–45.
  • Gupta, S., Mallick, D., Banerjee, K., Mukherjee, S., Sarkar, S., Lee, S. T., Basuchowdhuri, P., & Jana, S. S. (2022). D155Y substitution of SARS-CoV-2 ORF3a weakens binding with Caveolin-1. Computational and Structural Biotechnology Journal, 20, 766–778. https://doi.org/10.1016/j.csbj.2022.01.017
  • Gupta, S., Singh, A. K., Kushwaha, P. P., Prajapati, K. S., Shuaib, M., Senapati, S., & Kumar, S. (2021). Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies. Journal of Biomolecular Structure & Dynamics, 39(12), 4334–4345. https://doi.org/10.1080/07391102.2020.1776157
  • Harkey, T., Govind Kumar, V., Hettige, J., Tabari, S. H., Immadisetty, K., & Moradi, M. (2019). The Role of a crystallographically unresolved cytoplasmic loop in stabilizing the bacterial membrane insertase YidC2. Scientific Reports, 9(1), 14451. https://doi.org/10.1038/s41598-019-51052-9
  • Hostaš, J., Řezáč, J., & Hobza, P. (2013). On the performance of the semiempirical quantum mechanical PM6 and PM7 methods for noncovalent interactions. Chemical Physics Letters, 568-569, 161–166. https://doi.org/10.1016/j.cplett.2013.02.069
  • Huang, F., & Nau, W. M. (2003). A conformational flexibility scale for amino acids in peptides. Angewandte Chemie (International ed. in English), 42(20), 2269–2272. https://doi.org/10.1002/anie.200250684
  • Huang, X., Zheng, G., & Zhan, C. G. (2012). Microscopic binding of M5 muscarinic acetylcholine receptor with antagonists by homology modeling, molecular docking, and molecular dynamics simulation. The Journal of Physical Chemistry. B, 116(1), 532–541. https://doi.org/10.1021/jp210579b
  • Islam, M. J., Khan, A. M., Parves, M. R., Hossain, M. N., & Halim, M. A. (2019). Prediction of deleterious non-synonymous SNPs of human STK11 gene by combining algorithms, molecular docking, and molecular dynamics simulation. Scientific Reports, 9(1), 16426. https://doi.org/10.1038/s41598-019-52308-0
  • Islam, M. J., Parves, M. R., Mahmud, S., Tithi, F. A., & Reza, M. A. (2019). Assessment of structurally and functionally high-risk nsSNPs impacts on human bone morphogenetic protein receptor type IA (BMPR1A) by computational approach. Computational Biology and Chemistry, 80, 31–45. https://doi.org/10.1016/J.COMPBIOLCHEM.2019.03.004
  • Islam, M. J., Nawal Islam, N., Siddik Alom, M., Kabir, M., & Halim, M. A. (2022). A review on structural, non-structural, and accessory proteins of SARS-CoV-2: Highlighting drug target sites. Immunobiology, 228(1), 152302. https://doi.org/10.1016/J.IMBIO.2022.152302
  • Jain, K., Ghribi, O., & Delhommelle, J. (2021). Folding free-energy landscape of α-synuclein (35-97) via replica exchange molecular dynamics. Journal of Chemical Information and Modeling, 61(1), 432–443. https://doi.org/10.1021/acs.jcim.0c01278
  • Jones, P. M., & George, A. M. (2011). Molecular-dynamics simulations of the ATP/apo state of a multidrug ATP-binding cassette transporter provide a structural and mechanistic basis for the asymmetric occluded state. Biophysical Journal, 100(12), 3025–3034. https://doi.org/10.1016/j.bpj.2011.05.028
  • Kern, D. M., Sorum, B., Hoel, C. M., Sridharan, S., Remis, J. P., Toso, D. B., & Brohawn, S. G. (2020). Cryo-EM structure of the SARS-CoV-2 3a ion channel in lipid nanodiscs. bioRxiv (p. 2020.06.17.156554). bioRxiv. https://doi.org/10.1101/2020.06.17.156554
  • Kern, D. M., Sorum, B., Mali, S. S., Hoel, C. M., Sridharan, S., Remis, J. P., Toso, D. B., Kotecha, A., Bautista, D. M., & Brohawn, S. G. (2021). Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs. Nature Structural & Molecular Biology, 28(7), 573–582. https://doi.org/10.1038/s41594-021-00619-0
  • Khan, M. T., Islam, M. J., Parihar, A., Islam, R., Jerin, T. J., Dhote, R., Ali, M. A., Laura, F. K., & Halim, M. A. (2021). Immunoinformatics and molecular modeling approach to design universal multi-epitope vaccine for SARS-CoV-2. Informatics in Medicine Unlocked, 24, 100578. https://doi.org/10.1016/J.IMU.2021.100578
  • Khan, M. T., Khan, A., Rehman, A. U., Wang, Y., Akhtar, K., Malik, S. I., & Wei, D. Q. (2019). Structural and free energy landscape of novel mutations in ribosomal protein S1 (rpsA) associated with pyrazinamide resistance. Scientific Reports, 9(1), 7482. https://doi.org/10.1038/s41598-019-44013-9
  • Kumar, S., Sharma, P. P., Shankar, U., Kumar, D., Joshi, S. K., Pena, L., Durvasula, R., Kumar, A., Kempaiah, P., & Rathi, B. (2020). Discovery of new hydroxyethylamine analogs against 3CL pro protein target of SARS-CoV-2: Molecular docking, molecular dynamics simulation, and structure − activity relationship studies. Journal of Chemical Information and Modeling, 60(12), 5754–5770. https://doi.org/10.1021/acs.jcim.0c00326
  • Laskowski, R. A., MacArthur, M. W., Moss, D. S., & Thornton, J. M. (1993). PROCHECK: A program to check the stereochemical quality of protein structures. Journal of Applied Crystallography, 26(2), 283–291. https://doi.org/10.1107/S0021889892009944
  • Lebedeva, N. S., Gubarev, Y. A., Mamardashvili, G. M., Zaitceva, S. V., Zdanovich, S. A., Malyasova, A. S., Romanenko, J. V., Koifman, M. O., & Koifman, O. I. (2021). Theoretical and experimental study of interaction of macroheterocyclic compounds with ORF3a of SARS-CoV-2. Scientific Reports, 11(1), 19481. https://doi.org/10.1038/s41598-021-99072-8
  • Lee, Y.-B., Jung, M., Kim, J., Kang, M.-G., Kwak, C., Kim, J.-S., Mun, Y., Rhee, H.-W., & Mun, J.-Y. (2021). Endomembrane systems are reorganized by ORF3a and membrane (M) of SARS-CoV-2. BioRxiv, 2021.06.01.446555. https://doi.org/10.1101/2021.06.01.446555
  • Liao, S., Tan, K., Floyd, C., Bong, D., Pino, M. J., & Wu, C. (2021). Probing biased activation of mu-opioid receptor by the biased agonist PZM21 using all atom molecular dynamics simulation. Life Sciences, 269, 119026. https://doi.org/10.1016/j.lfs.2021.119026
  • Lins, L., Thomas, A., & Brasseur, R. (2003). Analysis of accessible surface of residues in proteins. Protein Science, 12(7), 1406–1417. https://doi.org/10.1110/ps.0304803
  • Luttens, A., Gullberg, H., Abdurakhmanov, E., Vo, D. D., Akaberi, D., Talibov, V. O., Nekhotiaeva, N., Vangeel, L., Jonghe, S. D., Jochmans, D., Krambrich, J., Tas, A., Lundgren, B., Gravenfors, Y., Craig, A. J., Atilaw, Y., Sandstr, A., Moodie, L. W. K., Lundkvist, Å., … Carlsson, J. (2022). Ultralarge virtual screening identifies SARS-CoV - 2 main protease inhibitors with broad-spectrum activity against coronaviruses. Journal of the American Chemical Society, 144(70), 2905–2920 https://doi.org/10.1021/jacs.1c08402
  • Lu, W., Zheng, B. J., Xu, K., Schwarz, W., Du, L., Wong, C. K. L., Chen, J., Duan, S., Deubel, V., & Sun, B. (2006). Severe acute respiratory syndrome-associated coronavirus 3a protein forms an ion channel and modulates virus release. Proceedings of the National Academy of Sciences of the United States of America, 103(33), 12540–12545. https://doi.org/10.1073/pnas.0605402103
  • Mahmud, S., Islam, M. J., Parves, M. R., Khan, M. A., Tabussum, L., Ahmed, S., Ali, M. A., Fakayode, S. O., & Halim, M. A. (2022). Designing potent inhibitors against the multidrug resistance P-glycoprotein. Journal of Biomolecular Structure & Dynamics, 40(19), 9403–9415. https://doi.org/10.1080/07391102.2021.1930159 https://doi.org/10.1080/07391102.2021.1930159
  • Mahtarin, R., Islam, S., Islam, M. J., Ullah, M. O., Ali, M. A., & Halim, M. A. (2022). Structure and dynamics of membrane protein in SARS-CoV-2. Journal of Biomolecular Structure & Dynamics, 40(10), 4725–4738. https://doi.org/10.1080/07391102.2020.1861983
  • Maier, J. A., Martinez, C., Kasavajhala, K., Wickstrom, L., Hauser, K. E., & Simmerling, C. (2015). ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB. Journal of Chemical Theory and Computation, 11(8), 3696–3713. https://doi.org/10.1021/acs.jctc.5b00255
  • Majumdar, P., & Niyogi, S. (2020). ORF3a mutation associated with higher mortality rate in SARS-CoV-2 infection. Epidemiology and Infection, 148, e262. https://doi.org/10.1017/S0950268820002599
  • Mark, P., & Nilsson, L. (2001). Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. The Journal of Physical Chemistry A, 105(43), 9954–9960. https://doi.org/10.1021/jp003020w
  • Matthes, D., & De Groot, B. L. (2009). Secondary structure propensities in peptide folding simulations: A systematic comparison of molecular mechanics interaction schemes. Biophysical Journal, 97(2), 599–608. https://doi.org/10.1016/j.bpj.2009.04.061
  • Meier, A., & Söding, J. (2015). Automatic prediction of Protein 3D structures by probabilistic multi-template homology modeling. PLoS Computational Biology, 11(10), e1004343. https://doi.org/10.1371/journal.pcbi.1004343
  • Mihăşan, M. (2010). Basic protein structure prediction for the biologist: A review. Archives of Biological Sciences, 62(4), 857–871. https://doi.org/10.2298/ABS1004857M
  • Minakshi, R., & Padhan, K. (2014). The YXXΦ motif within the severe acute respiratory syndrome coronavirus (SARS-CoV) 3a protein is crucial for its intracellular transport. Virology Journal, 11(1), 75. https://doi.org/10.1186/1743-422X-11-75
  • Minakshi, R., Padhan, K., Rani, M., Khan, N., Ahmad, F., & Jameel, S. (2009). The SARS coronavirus 3a protein causes endoplasmic reticulum stress and induces ligand-independent downregulation of the type 1 interferon receptor. PLoS One, 4(12), e8342. https://doi.org/10.1371/journal.pone.0008342
  • Mishra, C. B., Pandey, P., Sharma, R. D., Malik, M. Z., Mongre, R. K., Lynn, A. M., Prasad, R., Jeon, R., & Prakash, A. (2021). Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19: An integrated computational approach. Briefings in Bioinformatics, 22(2), 1346–1360. https://doi.org/10.1093/bib/bbaa378
  • Mortara, A., Mazzetti, S., Margonato, D., Delfino, P., Bersano, C., Catagnano, F., Lauriola, M., Grosso, P., Perseghin, G., & Ippoliti, G. (2021). Compassionate use of ruxolitinib in patients with SARS-Cov-2 infection not on mechanical ventilation: Short-term effects on inflammation and ventilation. Clinical and Translational Science, 14(3), 1062–1068. https://doi.org/10.1111/cts.12971
  • Padhan, K., Tanwar, C., Hussain, A., Hui, P. Y., Lee, M. Y., Cheung, C. Y., Peiris, J. S. M., & Jameel, S. (2007). Severe acute respiratory syndrome coronavirus Orf3a protein interacts with caveolin. The Journal of General Virology, 88(Pt 11), 3067–3077. https://doi.org/10.1099/vir.0.82856-0
  • Pal, S., Biswas, P., Ghosh, R., & Dam, S. (2021). In silico analysis and molecular identification of an anaphase-promoting complex homologue from human pathogen Entamoeba histolytica. Journal of Genetic Engineering and Biotechnology, 19(1), 133. https://doi.org/10.1186/s43141-021-00234-y
  • Pandey, B., Grover, A., & Sharma, P. (2018). Molecular dynamics simulations revealed structural differences among WRKY domain-DNA interaction in barley (Hordeum vulgare). BMC Genomics, 19(1), 132. https://doi.org/10.1186/s12864-018-4506-3
  • Parihar, A., Sonia, Z. F., Akter, F., Ali, M. A., Hakim, F. T., & Hossain, M. S. (2022). Phytochemicals-based targeting RdRp and main protease of SARS-CoV-2 using docking and steered molecular dynamic simulation: A promising therapeutic approach for tackling COVID-19. Computers in Biology and Medicine, 145, 105468. https://doi.org/10.1016/j.compbiomed.2022.105468
  • Pathak, R. K., Lim, B., Park, Y., & Kim, J.-M. (2022). Unraveling structural and conformational dynamics of DGAT1 missense nsSNPs in dairy cattle. Scientific Reports, 12(1), 4873. https://doi.org/10.1038/s41598-022-08833-6
  • Ren, Y., Shu, T., Wu, D., Mu, J., Wang, C., Huang, M., Han, Y., Zhang, X. Y., Zhou, W., Qiu, Y., & Zhou, X. (2020). The ORF3a protein of SARS-CoV-2 induces apoptosis in cells. Cellular & Molecular Immunology, 17(8), 881–883. Springer Nature. https://doi.org/10.1038/s41423-020-0485-9
  • Riccardi, L., Nguyen, P. H., & Stock, G. (2012). Construction of the free energy landscape of peptide aggregation from molecular dynamics simulations. Journal of Chemical Theory and Computation, 8(4), 1471–1479. https://doi.org/10.1021/ct200911w
  • Ruiz, D. M., Turowski, V. R., & Murakami, M. T. (2016). Effects of the linker region on the structure and function of modular GH5 cellulases. Scientific Reports, 6(June), 28504. https://doi.org/10.1038/srep28504
  • Saber-Ayad, M., Hammoudeh, S., Abu-Gharbieh, E., Hamoudi, R., Tarazi, H., Al-Tel, T. H., & Hamid, Q. (2021). Current status of baricitinib as a repurposed therapy for COVID-19. Pharmaceuticals, 14(7), 1–13. https://doi.org/10.3390/ph14070680
  • Sang, P., Du, X., Yang, L. Q., Meng, Z. H., & Liu, S. Q. (2017). Molecular motions and free-energy landscape of serine proteinase K in relation to its cold-adaptation: A comparative molecular dynamics simulation study and the underlying mechanisms. RSC Advances, 7(46), 28580–28590. https://doi.org/10.1039/C6RA23230B
  • Santhoshkumar, R., & Yusuf, A. (2020). In silico structural modeling and analysis of physicochemical properties of curcumin synthase (CURS1, CURS2, and CURS3) proteins of Curcuma longa. Journal of Genetic Engineering and Biotechnology, 18(1), 24. https://doi.org/10.1186/s43141-020-00041-x
  • Sharma, K., Surjit, M., Satija, N., Liu, B., Chow, V. T. K., & Lal, S. K. (2007). The 3a accessory protein of SARS coronavirus specifically interacts with the 5’’UTR of its genomic RNA, Using a unique 75 amino acid interaction domain. Biochemistry, 46(22), 6488–6499. https://doi.org/10.1021/bi062057p
  • Singh, R., Gurao, A., Rajesh, C., Mishra, S. K., Rani, S., Behl, A., Kumar, V., & Kataria, R. S. (2019). Comparative modeling and mutual docking of structurally uncharacterized heat shock protein 70 and heat shock factor-1 proteins in water buffalo. Veterinary World, 12(12), 2036–2045. https://doi.org/10.14202/vetworld.2019.2036-2045
  • Siu, K. L., Yuen, K. S., Castano-Rodriguez, C., Ye, Z. W., Yeung, M. L., Fung, S. Y., Yuan, S., Chan, C. P., Yuen, K. Y., Enjuanes, L., & Jin, D. Y. (2019). Severe acute respiratory syndrome Coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB Journal, 33(8), 8865–8877. https://doi.org/10.1096/fj.201802418R
  • Stebbing, J., Nievas, G. S., Falcone, M., Youhanna, S., Richardson, P., Ottaviani, S., Shen, J. X., Sommerauer, C., Tiseo, G., Ghiadoni, L., Virdis, A., Monzani, F., Rizos, L. R., Forfori, F., Céspedes, A. A., de Marco, S., Carrozzi, L., Lena, F., Sánchez-Jurado, P. M., … Lauschke, V. M. (2021). JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Science Advances, 7(1), 1–16. https://doi.org/10.1126/sciadv.abe4724
  • Tan, T. H., Patton, E., Munro, C. A., Corzo-Leon, D. E., Porter, A. J., & Palliyil, S. (2021). Monoclonal human antibodies that recognise the exposed n and c terminal regions of the often-overlooked SARS-Cov-2 ORF3a transmembrane protein. Viruses, 13(11), 2201. https://doi.org/10.3390/v13112201
  • Velazquez-Salinas, L., Zarate, S., Eberl, S., Gladue, D. P., Novella, I., & Borca, M. V. (2020). Positive selection of ORF1ab, ORF3a, and ORF8 genes drives the early evolutionary trends of SARS-CoV-2 during the 2020 COVID-19 pandemic. Frontiers in Microbiology, 11, 550674. https://doi.org/10.3389/fmicb.2020.550674
  • Voss, J. D., Skarzynski, M., McAuley, E. M., Maier, E. J., Gibbons, T., Fries, A. C., & Chapleau, R. R. (2021). Variants in SARS-CoV-2 associated with mild or severe outcome. Evolution, Medicine, and Public Health, 9(1), 267–275. https://doi.org/10.1093/emph/eoab019
  • Wang, R., Yang, X., Chang, M., Xue, Z., Wang, W., Bai, L., Zhao, S., & Liu, E. (2021). ORF3a protein of severe acute respiratory syndrome coronavirus 2 inhibits interferon-activated Janus kinase/signal transducer and activator of transcription signaling via elevating suppressor of cytokine signaling 1. Frontiers in Microbiology, 12(September), 752597. https://doi.org/10.3389/fmicb.2021.752597
  • Wang, R., & Zheng, Q. (2020). Multiple molecular dynamics simulations of the inhibitor GRL-02031 complex with wild type and mutant HIV-1 protease reveal the binding and drug-resistance mechanism. Langmuir, 36(46), 13817–13832. https://doi.org/10.1021/acs.langmuir.0c02151
  • Wang, R., & Zheng, Q. (2022). Multiple molecular dynamics simulations and energy analysis unravel the dynamic properties and binding mechanism of mutants HIV-1 protease with DRV and CA-p2. Microbiology Spectrum, 10(2), e0074821. https://doi.org/10.1128/spectrum.00748-21
  • Xu, H., Akinyemi, I. A., Chitre, S. A., Loeb, J. C., Lednicky, J. A., McIntosh, M. T., & Bhaduri-McIntosh, S. (2022). SARS-CoV-2 viroporin encoded by ORF3a triggers the NLRP3 inflammatory pathway. Virology, 568(January), 13–22. https://doi.org/10.1016/j.virol.2022.01.003
  • Xu, J., Zhao, S., Teng, T., Abdalla, A. E., Zhu, W., Xie, L., Wang, Y., & Guo, X. (2020). Systematic comparison of two animal-to-human transmitted human coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses, 12(2), 244. https://doi.org/10.3390/v12020244
  • Xue, M., & Feng, L. (2021). The role of unfolded protein response in coronavirus infection and its implications for drug design. Frontiers in Microbiology, 12, 808593. https://doi.org/10.3389/fmicb.2021.808593
  • Yoshimoto, F. K. (2020). The proteins of severe acute respiratory syndrome coronavirus-2 (SARS CoV-2 or n-COV19), the cause of COVID-19. The Protein Journal, 39(3), 198–216. https://doi.org/10.1007/s10930-020-09901-4
  • Zhang, J., Ejikemeuwa, A., Gerzanich, V., Nasr, M., Tang, Q., Simard, J. M., & Zhao, R. Y. (2022). Understanding the role of SARS-CoV-2 ORF3a in viral pathogenesis and COVID-19. Frontiers in Microbiology, 13(March), 854567. https://doi.org/10.3389/fmicb.2022.854567
  • Zhang, Y. (2008). I-TASSER server for protein 3D structure prediction. BMC Bioinformatics, 9(1), 40. https://doi.org/10.1186/1471-2105-9-40
  • Zhang, Y., Sun, H., Pei, R., Mao, B., Zhao, Z., Li, H., Lin, Y., & Lu, K. (2021). The SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes. Cell Discovery, 7(1), 31. https://doi.org/10.1038/s41421-021-00268-z

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