User:Ann Taylor/SARS-CoV2 MPro

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(New page: ==SARS-CoV2 MPro== <StructureSection load='6M03' size='340' side='right' caption='Main Protease from SARS-CoV2' scene=''> <ref>PMID:35380892</ref> to the rescue. ==Peptidic inhibitors=...)
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<StructureSection load='6M03' size='340' side='right' caption='Main Protease from SARS-CoV2' scene=''>
<StructureSection load='6M03' size='340' side='right' caption='Main Protease from SARS-CoV2' scene=''>
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<ref>PMID:35380892</ref> to the rescue.
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Like many viruses, SARS-CoV2 synthesizes its proteins in long, polypeptide chains that must be cleaved to form functional proteins. The coronavirus ORF 1 polyprotein can be divided into an N-terminal region that is processed by one or two Papain-like proteases and a C-terminal region which is processed by the main protease. <ref> Enjuanes, L., (2005). Coronavirus replication and reverse genetics Berlin; New York: Springer, S. 69-78. </ref> While papain-like protease(s) cleave only three sites, the main protease cleaves 11 sites in the polyprotein to generate functional proteins. Additionally, the main protease cleaves its own N- and C-terminal autoprocessing sites. The cleaved functional proteins include viral enzymes needed for replication such as the RNA-dependant RNA polymerase, a helicase and other non-structural or accessory proteins such as an exoribonuclease, an endoribonuclease, a ssRNA binding protein and a 2’-O-ribose methyltransferase. <ref> Muramatsu, T., Takemoto, C., Kim, Y.-T., Wang, H., Nishii, W., Terada, T., Shirouzu, M. & Yokoyama, S. (2016). Proc Natl Acad Sci U S A. 113, 12997–13002. </ref>
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== Overall Structure and Active Site of M protease ==
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The main protease is a cysteine protease that is essential for the viral life cycle. It is folded like an augmented serine-protease which forms a homodimer consisting of the perpendicular protomers A and B. One protomer consists of <scene name='86/866577/Domains/2'>three domains</scene>. Domain I and II (N-terminal domain) form an antiparallel chymotrypsin-like ß-barrel structure. Domain III (C-terminal end) consist of five alpha-helices arranged in an antiparallel cluster. <ref> Yang, H., Yang, M., Ding, Y., Liu, Y., Lou, Z., Zhou, Z., Sun, L., Mo, L., Ye, S., Pang, H., Gao, G. F., Anand, K., Bartlam, M., Hilgenfeld, R. & Rao, Z. (2003). Proc Natl Acad Sci U S A. 100, 13190–13195. </ref> <ref name=”Xu”> Xu, T., Ooi, A., Lee, H. C., Wilmouth, R., Liu, D. X. & Lescar, J. (2005). Acta Crystallogr Sect F Struct Biol Cryst Commun. 61, 964–966. </ref> For maximal protease activity, the protease forms a homodimer as the substrate binding site is located in a catalytic cleft between the two N-terminal ß-barrel structures (between domain I and II). The substrate binding site involves a <scene name='86/866577/Active_site/2'>catalytic dyad</scene> consisting of the residues Cys145 and His41. The N- and C-terminal domains are connected by a long loop. <ref> Anand, K., Ziebuhr, J., Wadhwani, P., Mesters, J. R. & Hilgenfeld, R. (2003). Science. 300, 1763–1767. </ref> N-terminal residues of each protomer which are called N-finger, make contact between the N- and C-terminal domains of the other protomer and thus are necessary for dimerization.
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<ref> Yang, H., Xie, W., Xue, X., Yang, K., Ma, J., Liang, W., Zhao, Q., Zhou, Z., Pei, D., Ziebuhr, J., Hilgenfeld, R., Yuen, K. Y., Wong, L., Gao, G., Chen, S., Chen, Z., Ma, D., Bartlam, M. & Rao, Z. (2005). PLoS Biol. 3. </ref> S1 is a <scene name='86/866577/Binding_pocket/1'>substrate binding subsite pocket</scene> which lies next to the catalytic dyad and consists of the side chains Phe 140, His 163 and the main chains of Glu166, Asn142, Gly 143 and His172. It confers absolute specificity for the Gln-P1 substrate residue on the enzyme as the carbonyl oxygen of Gln-P1 is stabilized by an <scene name='86/866577/Oxyanion_hole/1'>oxyanion hole</scene> which is formed by amide groups of Gly143 and the catalytic Cys145. <ref> Gorbalenya, A. E., Snijder, E. J. & Ziebuhr, J. (2000). Journal of General Virology. 81, 853–879. </ref> <ref> Xue, X., Yu, H., Yang, H., Xue, F., Wu, Z., Shen, W., Li, J., Zhou, Z., Ding, Y., Zhao, Q., Zhang, X. C., Liao, M., Bartlam, M. & Rao, Z. (2008). Journal of Virology. 82, 2515–2527. </ref> Hence, polyproteins are cleaved within the Leu-Gln↓(Ser, Ala, Gly) sequence. <ref> Rut, W., Groborz, K., Zhang, L., Sun, X., Zmudzinski, M., Hilgenfeld, R. & Drag, M. (2020). BioRxiv. 2020.03.07.981928. </ref>
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<ref>PMID:35380892</ref>

Revision as of 21:14, 20 February 2023

SARS-CoV2 MPro

Main Protease from SARS-CoV2

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References

  1. ↑ Enjuanes, L., (2005). Coronavirus replication and reverse genetics Berlin; New York: Springer, S. 69-78.
  2. ↑ Muramatsu, T., Takemoto, C., Kim, Y.-T., Wang, H., Nishii, W., Terada, T., Shirouzu, M. & Yokoyama, S. (2016). Proc Natl Acad Sci U S A. 113, 12997–13002.
  3. ↑ Yang, H., Yang, M., Ding, Y., Liu, Y., Lou, Z., Zhou, Z., Sun, L., Mo, L., Ye, S., Pang, H., Gao, G. F., Anand, K., Bartlam, M., Hilgenfeld, R. & Rao, Z. (2003). Proc Natl Acad Sci U S A. 100, 13190–13195.
  4. ↑ Xu, T., Ooi, A., Lee, H. C., Wilmouth, R., Liu, D. X. & Lescar, J. (2005). Acta Crystallogr Sect F Struct Biol Cryst Commun. 61, 964–966.
  5. ↑ Anand, K., Ziebuhr, J., Wadhwani, P., Mesters, J. R. & Hilgenfeld, R. (2003). Science. 300, 1763–1767.
  6. ↑ Yang, H., Xie, W., Xue, X., Yang, K., Ma, J., Liang, W., Zhao, Q., Zhou, Z., Pei, D., Ziebuhr, J., Hilgenfeld, R., Yuen, K. Y., Wong, L., Gao, G., Chen, S., Chen, Z., Ma, D., Bartlam, M. & Rao, Z. (2005). PLoS Biol. 3.
  7. ↑ Gorbalenya, A. E., Snijder, E. J. & Ziebuhr, J. (2000). Journal of General Virology. 81, 853–879.
  8. ↑ Xue, X., Yu, H., Yang, H., Xue, F., Wu, Z., Shen, W., Li, J., Zhou, Z., Ding, Y., Zhao, Q., Zhang, X. C., Liao, M., Bartlam, M. & Rao, Z. (2008). Journal of Virology. 82, 2515–2527.
  9. ↑ Rut, W., Groborz, K., Zhang, L., Sun, X., Zmudzinski, M., Hilgenfeld, R. & Drag, M. (2020). BioRxiv. 2020.03.07.981928.
  10. ↑ Zhao Y, Zhu Y, Liu X, Jin Z, Duan Y, Zhang Q, Wu C, Feng L, Du X, Zhao J, Shao M, Zhang B, Yang X, Wu L, Ji X, Guddat LW, Yang K, Rao Z, Yang H. Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2. Proc Natl Acad Sci U S A. 2022 Apr 19;119(16):e2117142119. doi:, 10.1073/pnas.2117142119. Epub 2022 Apr 5. PMID:35380892 doi:http://dx.doi.org/10.1073/pnas.2117142119

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Ann Taylor

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