View source for User:Ann Taylor/SARS-CoV2 MPro

==SARS-CoV2 MPro==
<StructureSection load='6y2e' size='340' side='right' caption='Main Protease from SARS-CoV2' scene=''>

Like many viruses, SARS-CoV2 synthesizes its proteins in long, polypeptide chains that must be cleaved to form functional proteins. SARS-CoV2 uses two different proteases, a papain-like protease and 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, and is the focus of this page. 
 
== Overall Structure and Active Site of M protease ==

The main protease is a cysteine protease that is essential for the viral life cycle. It is forms a <scene name='95/952725/Dimer/1'>homodimer</scene> arranged perpendicularly. Each protein chain has <scene name='86/866577/Domains/2'>three domains</scene>. Domains I and II 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>  The substrate binds in a <scene name='95/952725/Substrate_binding_groove/1'>channel</scene> between Domains I and II.  Most of the residues in the channel are neutral (shown in white) with a few acidic residues.  S1 is the <scene name='95/952725/S1_with_peptide/1'>substrate binding site</scene> and consists of the side chains Phe 140, His 163 and the backbone atoms 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 interactions with the <scene name='95/952725/Oxyanion_w_substrate/1'>backbone amide</scene> 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>

The active site involves a <scene name='86/866577/Active_site/2'>catalytic dyad</scene> consisting of the residues Cys145 and His41.  It forms a covalent intermediate with the substrate in a similar fashion to a [[serine protease]].
 
==Peptidic inhibitors==
A number of structures of MPro with candidate inhibitors have been determined, including <scene name='42/426139/6xa4/1'>6XA4</scene>, <scene name='42/426139/6xfn/1'>6XFN</scene>, <scene name='42/426139/6xbg/1'>6XBG</scene>, <scene name='42/426139/6xbh/1'>6XBH</scene>, <scene name='42/426139/6xbi/1'>6XBI</scene>, and 6WTT.





</StructureSection>
== References ==
<references/>