Proteopedia - User contributions [en]

SARS-CoV-2 enzyme NendoU

2020-06-03T11:29:14Z

Gianluca Santoni:

<SX viewer='molstar' load='6vww' size='340' side='right' caption='This is the structure of NendoU' scene=''>

== Function ==
'''Uridylate-specific endoribonuclease (NendoU)'''

SARS-CoV-2 non-structural protein 15 (Nsp15) is a nidoviral RNA uridylate-specific endoribonuclease (NendoU). Its C-terminal catalytic domain belongs to the EndoU family, meaning it produces 2’-3’ cyclic phosphodiester and 5’-hydroxytermini following RNA endonuclease activity on single- and double-stranded RNA and is specific for uridine <ref>PMID:21422822</ref>. Mn2+ dependence has been observed in other members of the NendoU subfamily.

The exact functional relevance of Nsp15 is currently unknown. Nsp15-deficient corona viruses remain viable and replicating <ref name="structure">PMID:32304108</ref>. However, conflicting studies have been published on Nsp15’s role in interfering with the innate immune response <ref>PMID:28484023</ref>,<ref>PMID:31351410</ref> and it has been suggested that Nsp15 degrades viral RNA as a method to hide it from host defences <ref name="structure" />.

== Disease ==

SARS-CoV-2 is the cause of a global COVID-19 pandemic which started in 2019.

== Relevance ==

SARS-CoV-2 NendoU (Nsp15) represents a potential drug target for treatment of COVID-19, of particular interest is interfering with oligomerisation to prevent formation of the hexamer.

== Structural highlights ==

SARS-CoV-2 Nsp15 features three distinct domains. First, an N-terminal oligomerisation domain composed of an anti-parallel β-sheet (β1-3) wrapped around two helices (α1-2). This is followed by a middle domain made of three β-hairpins (β5-7, β7-8, and β12-13), a mixed β-sheet (β4, β9, β,10, β11, β15, and β15), and three α-helices (α3, η4, and α5). The final domain is the catalytic NendoU domain comprised of two anti-parallel β-sheets (β16-18 and β19-21) which form a concave surface flanked by five α-helices (α6-10). Six conserved residues make up the active site of Nsp15 (His235, His250, Lys290, Thr341, Tyr343, and Ser294) and are expected to coordinate a manganese ion. However, currently available structures have a magnesium ion modelled as manganese was not present in the crystallisation solution <ref name="structure" />.

SARS-CoV-2 Nsp15 forms a hexamer of monomers. Each subunit domain contributes to the oligomer interface and the assembly is stabilised through interactions with the N-terminal oligomerisation domain. This forms a 100 Å long 10-15 Å wide channel down the three-fold axis which is open to solvent from the top, bottom and three separate side openings in the middle of the hexamer.

SARS-CoV-2 Nsp15 from SARS-CoV-2 resembles previously observed endonucleases from SARS-CoV (0.52 Å RMSD, PDBID: 2H85) and MERS-CoV (1.16 Å RMSD, PDBID: 5YVD) <ref name="structure" />.

== See also ==
[[Coronavirus_Disease 2019 (COVID-19)]]
__NOTOC__
</SX>
== References ==
<references/>

SARS-CoV-2 protein S

2020-04-21T07:34:54Z

Gianluca Santoni: Changed to Mol*

==Spike Glycoprotein==

<SX viewer='molstar' load='6vsb' size='323' side='right' caption='Cryo-EM reconstruction of the spike. It consists of 3 monomers of the Spike glycoprotein (carbohydrates displayed as blue cubes) (PDB-ID [[6vsb]]).' scene='84/842090/6vsb_cube_carboydrages/1'>

==Function==
The homotrimeric spike glycoprotein on the virus envelope mediates the entry into cell. Every monomer consists of the two subunits S1 and S2. SARS-CoV-2 spike S1 subunit binds the cellular receptor called angiotensin converting enzyme 2 (ACE2). Binding triggers a cascade of events leading to the fusion of cell and virus membrane. After the prefusion trimer is destabilized, the S1 subunit is shedded leading to transition of the S2 subunit to a stable postfusion conformation. To engage a host cell receptor, the receptor-binding domain (RBD) of S1 undergoes hinge-like conformational rearrangement that transiently hide or expose the residues necessary for receptor binding. <ref name="Wrapp"> Wrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S.; Goldsmith, Jory A.; Hsieh, Ching-Lin; Abiona, Olubukola et al. (2020): Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. In: Science 367 (6483), S. 1260–1263. DOI: 10.1126/science.abb2507.</ref>

==Structure Description==

Spike subunits S1 and S2 can be divided into several subdomains. The S1 subunit comprises a signal sequence (SS) on the N-terminal end followed by a N-terminal domain (NTD) and the receptor binding domain (RBD). After two small subdomains (SD1/2), we find two protease cleavage sites (S1/S2 and S2’).The S2 subunit is composed of a fusion peptide (FP), two heptad repeats (HR1 and 2), a central helix (CH), a connector domain (CD), a transmembrane domain (TM) and the cytoplasmic tail (CT). <ref name="Wrapp" />

The structure of the receptor binding domain (RBD), in complex with the human ACE2 receptor, shows that interaction happens via the spike protein RBD and the ACE2 N-terminal peptidase domain. The RBD consists of a twisted five stranded antiparallel β-sheet (β1, β2, β3, β4 und β7) forming the core together with short connecting helices and loops. The spike receptor binding motif (RBM), containing most of the ACE2 contacting residues, is located as an extended insertion between the β4 and β7 strands consisting of short β-sheets (β5 and β6), α-helices (α4 and α5) and loops. The ACE2 N-terminal peptidase domain has two lobes that form the substrate binding site. The contact between RBM and ACE2 is made at the bottom side of the ACE2 small lobe, with a concave outer surface in the RBM accommodating the N-terminal helix of the ACE2 and thus generating an interface of 1687 Å^2. This interface contains a network of different interactions, including hydrophilic interactions with 13 hydrogen bonds and 2 salt bridges. Key residues for for receptor binding include the amino acids Leu544, Phe486, Gln493, and Asn 501. Leu 544 interacts with ACE2 residues Asp30, Lys31 and His34. Phe486, interacts with ACE2 GLN24, Leu79, Met82 (by van der Waals forces) and Tyr 83. Gln 493 forms a hydrogen bond with ACE2 Glu35 and interacts with Lys31 and His34. Another Hydrogen bond is formed between ACE2 Tyr 41 and Asn501 of one α-helix of the RBM. Further, Asn501 also interacts with the amino acid residues Lys353, Gly354 and Asp355. Outside the RBM, there is another unique ACE2-interacting residue Lys417, forming a salt bride with ACE2 Asp30. <ref name="Lan">Lan, Jun; Ge, Jiwan; Yu, Jinfang; Shan, Sisi; Zhou, Huan; Fan, Shilong et al. (2020): Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. In: Nature. DOI: 10.1038/s41586-020-2180-5. </ref> <ref> Yan, Renhong; Zhang, Yuanyuan; Li, Yaning; Xia, Lu; Guo, Yingying; Zhou, Qiang (2020): Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. In: Science 367 (6485), S. 1444–1448. DOI: 10.1126/science.abb2762.
</ref>

==Fusion and Entry Mechanism==

The task of the spike protein is to initiate the fusion and entry with/ into the host cell. A key role in mediating these processes are the domains S-HR1 and S-HR2. The exact mechanism of entry and fusion of SARS-CoV-2 with/ into the host cell is still not fully known but it could be possible that the 2019-nCoV may have similar membrane fusion mechanism as that of SARS-CoV. The putative antiviral mechanism is, that after binding of RBD S1 subunit of 2019-nCoV spike protein to the receptor ACE2 on the host cell, S2 subunit changes conformation by inserting FP into the cell membranes, triggering the association between the HR1 and HR2 domains to form a six-helix-bundle, which brings the viral and cellular membranes in close proximity for fusion.<ref> Xia, Shuai; Zhu, Yun; Liu, Meiqin; Lan, Qiaoshuai; Xu, Wei; Wu, Yanling et al. (2020): Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein. In: Cellular & molecular immunology. DOI: 10.1038/s41423-020-0374-2.</ref>

==Glycosilation of the Spike Protein==

Coronavirus spike proteins are densely decorated by heterogenous N-linked glycans protruding from the trimer surface. SARS-CoV-2 S comprises 22 N-linked glycosylation sequons per protomer. N-linked glycans play a key role in proper protein folding and in priming by host proteases <ref> Walls, Alexandra C.; Park, Young-Jun; Tortorici, M. Alejandra; Wall, Abigail; McGuire, Andrew T.; Veesler, David (2020): Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. In: Cell. DOI: 10.1016/j.cell.2020.02.058.</ref> Since glycans can shield the amino acid residues and other epitopes from cells and antibody recognition, glycosylation can enable the coronavirus to evade both the innate and adaptive immune responses. <ref name="Lan" /> <ref>Shen, Shuo; Tan, Timothy H. P.; Tan, Yee-Joo (2007): Expression, glycosylation, and modification of the spike (S) glycoprotein of SARS CoV. In: Methods in molecular biology (Clifton, N.J.) 379, S. 127–135. DOI: 10.1007/978-1-59745-393-6_9.</ref>

</SX>

== References ==
<references/>

SARS-CoV-2 protein S

2020-04-21T05:55:09Z

Gianluca Santoni:

==Spike Glycoprotein==
<StructureSection load='6vsb' size='350' side='right' caption='Cryo-EM reconstruction of the spike. It consists of 3 monomers of the Spike glycoprotein (pdb code 6vsb)'>

==Function==
The homotrimeric spike glycoprotein on the virus envelope mediates the entry into cell. Every monomer consists of the two subunits S1 and S2. SARS-CoV-2 spike S1 subunit binds the cellular receptor called angiotensin converting enzyme 2 (ACE2). Binding triggers a cascade of events leading to the fusion of cell and virus membrane. After the prefusion trimer is destabilized, the S1 subunit is shedded leading to transition of the S2 subunit to a stable postfusion conformation. To engage a host cell receptor, the receptor-binding domain (RBD) of S1 undergoes hinge-like conformational rearrangement that transiently hide or expose the residues necessary for receptor binding. <ref name="Wrapp"> Wrapp, Daniel; Wang, Nianshuang; Corbett, Kizzmekia S.; Goldsmith, Jory A.; Hsieh, Ching-Lin; Abiona, Olubukola et al. (2020): Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. In: Science 367 (6483), S. 1260–1263. DOI: 10.1126/science.abb2507.</ref>

==Structure Description==

Spike subunits S1 and S2 can be divided into several subdomains. The S1 subunit comprises a signal sequence (SS) on the N-terminal end followed by a N-terminal domain (NTD) and the receptor binding domain (RBD). After two small subdomains (SD1/2), we find two protease cleavage sites (S1/S2 and S2’).The S2 subunit is composed of a fusion peptide (FP), two heptad repeats (HR1 and 2), a central helix (CH), a connector domain (CD), a transmembrane domain (TM) and the cytoplasmic tail (CT). <ref name="Wrapp" />

The structure of the receptor binding domain (RBD), in complex with the human ACE2 receptor, shows that interaction happens via the spike protein RBD and the ACE2 N-terminal peptidase domain. The RBD consists of a twisted five stranded antiparallel β-sheet (β1, β2, β3, β4 und β7) forming the core together with short connecting helices and loops. The spike receptor binding motif (RBM), containing most of the ACE2 contacting residues, is located as an extended insertion between the β4 and β7 strands consisting of short β-sheets (β5 and β6), α-helices (α4 and α5) and loops. The ACE2 N-terminal peptidase domain has two lobes that form the substrate binding site. The contact between RBM and ACE2 is made at the bottom side of the ACE2 small lobe, with a concave outer surface in the RBM accommodating the N-terminal helix of the ACE2 and thus generating an interface of 1687 Å^2. This interface contains a network of different interactions, including hydrophilic interactions with 13 hydrogen bonds and 2 salt bridges. Key residues for for receptor binding include the amino acids Leu544, Phe486, Gln493, and Asn 501. Leu 544 interacts with ACE2 residues Asp30, Lys31 and His34. Phe486, interacts with ACE2 GLN24, Leu79, Met82 (by van der Waals forces) and Tyr 83. Gln 493 forms a hydrogen bond with ACE2 Glu35 and interacts with Lys31 and His34. Another Hydrogen bond is formed between ACE2 Tyr 41 and Asn501 of one α-helix of the RBM. Further, Asn501 also interacts with the amino acid residues Lys353, Gly354 and Asp355. Outside the RBM, there is another unique ACE2-interacting residue Lys417, forming a salt bride with ACE2 Asp30. <ref name="Lan">Lan, Jun; Ge, Jiwan; Yu, Jinfang; Shan, Sisi; Zhou, Huan; Fan, Shilong et al. (2020): Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. In: Nature. DOI: 10.1038/s41586-020-2180-5. </ref> <ref> Yan, Renhong; Zhang, Yuanyuan; Li, Yaning; Xia, Lu; Guo, Yingying; Zhou, Qiang (2020): Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. In: Science 367 (6485), S. 1444–1448. DOI: 10.1126/science.abb2762.
</ref>

==Fusion and Entry Mechanism==

The task of the spike protein is to initiate the fusion and entry with/ into the host cell. A key role in mediating these processes are the domains S-HR1 and S-HR2. The exact mechanism of entry and fusion of SARS-CoV-2 with/ into the host cell is still not fully known but it could be possible that the 2019-nCoV may have similar membrane fusion mechanism as that of SARS-CoV. The putative antiviral mechanism is, that after binding of RBD S1 subunit of 2019-nCoV spike protein to the receptor ACE2 on the host cell, S2 subunit changes conformation by inserting FP into the cell membranes, triggering the association between the HR1 and HR2 domains to form a six-helix-bundle, which brings the viral and cellular membranes in close proximity for fusion.<ref> Xia, Shuai; Zhu, Yun; Liu, Meiqin; Lan, Qiaoshuai; Xu, Wei; Wu, Yanling et al. (2020): Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein. In: Cellular & molecular immunology. DOI: 10.1038/s41423-020-0374-2.</ref>

==Glycosilation of the Spike Protein==

Coronavirus spike proteins are densely decorated by heterogenous N-linked glycans protruding from the trimer surface. SARS-CoV-2 S comprises 22 N-linked glycosylation sequons per protomer. N-linked glycans play a key role in proper protein folding and in priming by host proteases <ref> Walls, Alexandra C.; Park, Young-Jun; Tortorici, M. Alejandra; Wall, Abigail; McGuire, Andrew T.; Veesler, David (2020): Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. In: Cell. DOI: 10.1016/j.cell.2020.02.058.</ref> Since glycans can shield the amino acid residues and other epitopes from cells and antibody recognition, glycosylation can enable the coronavirus to evade both the innate and adaptive immune responses. <ref name="Lan" /> <ref>Shen, Shuo; Tan, Timothy H. P.; Tan, Yee-Joo (2007): Expression, glycosylation, and modification of the spike (S) glycoprotein of SARS CoV. In: Methods in molecular biology (Clifton, N.J.) 379, S. 127–135. DOI: 10.1007/978-1-59745-393-6_9.</ref>

</StructureSection>

== References ==
<references/>

SARS-CoV-2 Coronavirus Main Protease

2020-04-07T08:36:42Z

Gianluca Santoni:

== Main Protease ==

<StructureSection load='6y2e' size='350' side='right' caption='Main protease from SARS-CoV2 (PDB entry [[6y2e]])' scene=''>

SARS-CoV-2 is a positive-stranded RNA virus with nucleocapsid which belongs to betacoronaviruses. The 30 kb long +ssRNA contains a 5’-cap structure and a 3’-poly-A tail. After membrane fusion, the viral +ssRNA is released into the cytoplasm and translated into two polyproteins pp1a and pp1ab. <ref> Guo, Y.-R., Cao, Q.-D., Hong, Z.-S., Tan, Y.-Y., Chen, S.-D., Jin, H.-J., Tan, K.-S., Wang, D.-Y. & Yan, Y. (2020). Mil Med Res. 7. </ref> <ref> Cascella, M., Rajnik, M., Cuomo, A., Dulebohn, S. C. & Di Napoli, R. (2020). StatPearls, Vol. p. Treasure Island (FL): StatPearls Publishing. </ref> Papain-like protease(s) and the main protease (also called 3C-like protease [3CLpro]]) are essential for processing the two polyproteins pp1a and pp1ab.
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>

== Overall Structure and Active Centre of 3CLpro ==

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 three domains. 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 catalytic dyad 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.
<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 substrate binding subsite pocket 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 oxyanion hole 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>

== 3CLpro as Potential Drug Target ==

Due to a new outbreak of pulmonary diseases caused by SARS-CoVid-2, the development of new drugs is essential for containment of the viral spread. One promising drug target among coronaviruses is the main protease, as it is essential for processing the polyproteins translated from the viral RNA. Inhibiting this enzyme would block the viral replication and is unlikely to be toxic, as no human proteases with similar cleavage specificity are known. <ref> Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K. & Hilgenfeld, R. (2020). Science. </ref> The potential inhibitor classes can be divided into two classes based on their chemical structures. The first class involves peptide chains that fit the catalytic site of the enzyme by making a covalent link with Cys145, therefore blocking substrate binding. The second class consists of small organic compounds that bind the active site and hence act as competitive inhibitors. Thus, the substrate can not enter the active site cavity. A potential drug which belongs to the second class is Lopinavir, a HIV1 protease inhibitor which seems to be a promising candidate for the treatment of coronavirus infections. <ref> Dayer, M. R., Taleb-Gassabi, S. & Dayer, M. S. (2017). Lopinavir; A Potent Drug against Coronavirus Infection: Insight from Molecular Docking Study. </ref>

</StructureSection>

== References ==

<references/>

SARS-CoV-2 Coronavirus Main Protease

2020-04-07T08:35:27Z

Gianluca Santoni:

<StructureSection load='6y2e' size='350' side='right' caption='Main protease from SARS-CoV2 (PDB entry [[6y2e]])' scene=''>

== Main Protease ==

SARS-CoV-2 is a positive-stranded RNA virus with nucleocapsid which belongs to betacoronaviruses. The 30 kb long +ssRNA contains a 5’-cap structure and a 3’-poly-A tail. After membrane fusion, the viral +ssRNA is released into the cytoplasm and translated into two polyproteins pp1a and pp1ab. <ref> Guo, Y.-R., Cao, Q.-D., Hong, Z.-S., Tan, Y.-Y., Chen, S.-D., Jin, H.-J., Tan, K.-S., Wang, D.-Y. & Yan, Y. (2020). Mil Med Res. 7. </ref> <ref> Cascella, M., Rajnik, M., Cuomo, A., Dulebohn, S. C. & Di Napoli, R. (2020). StatPearls, Vol. p. Treasure Island (FL): StatPearls Publishing. </ref> Papain-like protease(s) and the main protease (also called 3C-like protease [3CLpro]]) are essential for processing the two polyproteins pp1a and pp1ab.
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>

== Overall Structure and Active Centre of 3CLpro ==

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 three domains. 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 catalytic dyad 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.
<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 substrate binding subsite pocket 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 oxyanion hole 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>

== 3CLpro as Potential Drug Target ==

Due to a new outbreak of pulmonary diseases caused by SARS-CoVid-2, the development of new drugs is essential for containment of the viral spread. One promising drug target among coronaviruses is the main protease, as it is essential for processing the polyproteins translated from the viral RNA. Inhibiting this enzyme would block the viral replication and is unlikely to be toxic, as no human proteases with similar cleavage specificity are known. <ref> Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K. & Hilgenfeld, R. (2020). Science. </ref> The potential inhibitor classes can be divided into two classes based on their chemical structures. The first class involves peptide chains that fit the catalytic site of the enzyme by making a covalent link with Cys145, therefore blocking substrate binding. The second class consists of small organic compounds that bind the active site and hence act as competitive inhibitors. Thus, the substrate can not enter the active site cavity. A potential drug which belongs to the second class is Lopinavir, a HIV1 protease inhibitor which seems to be a promising candidate for the treatment of coronavirus infections. <ref> Dayer, M. R., Taleb-Gassabi, S. & Dayer, M. S. (2017). Lopinavir; A Potent Drug against Coronavirus Infection: Insight from Molecular Docking Study. </ref>

</StructureSection>

== References ==

<references/>

SARS-CoV-2 Coronavirus Main Protease

2020-04-06T15:20:28Z

Gianluca Santoni:

== Main Protease ==

SARS-CoV-2 is a positive-stranded RNA virus with nucleocapsid which belongs to betacoronaviruses. The 30 kb long +ssRNA contains a 5’-cap structure and a 3’-poly-A tail. After membrane fusion, the viral +ssRNA is released into the cytoplasm and translated into two polyproteins pp1a and pp1ab. <ref> Guo, Y.-R., Cao, Q.-D., Hong, Z.-S., Tan, Y.-Y., Chen, S.-D., Jin, H.-J., Tan, K.-S., Wang, D.-Y. & Yan, Y. (2020). Mil Med Res. 7. </ref> <ref> Cascella, M., Rajnik, M., Cuomo, A., Dulebohn, S. C. & Di Napoli, R. (2020). StatPearls, Vol. p. Treasure Island (FL): StatPearls Publishing. </ref> Papain-like protease(s) and the main protease (also called 3C-like protease [3CLpro]]) are essential for processing the two polyproteins pp1a and pp1ab.
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>

== Overall Structure and Active Centre of 3CLpro ==

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 three domains. 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 catalytic dyad 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.
<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 substrate binding subsite pocket 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 oxyanion hole 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>

== 3CLpro as Potential Drug Target ==

Due to a new outbreak of pulmonary diseases caused by SARS-CoVid-2, the development of new drugs is essential for containment of the viral spread. One promising drug target among coronaviruses is the main protease, as it is essential for processing the polyproteins translated from the viral RNA. Inhibiting this enzyme would block the viral replication and is unlikely to be toxic, as no human proteases with similar cleavage specificity are known. <ref> Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K. & Hilgenfeld, R. (2020). Science. </ref> The potential inhibitor classes can be divided into two classes based on their chemical structures. The first class involves peptide chains that fit the catalytic site of the enzyme by making a covalent link with Cys145, therefore blocking substrate binding. The second class consists of small organic compounds that bind the active site and hence act as competitive inhibitors. Thus, the substrate can not enter the active site cavity. A potential drug which belongs to the second class is Lopinavir, a HIV1 protease inhibitor which seems to be a promising candidate for the treatment of coronavirus infections. <ref> Dayer, M. R., Taleb-Gassabi, S. & Dayer, M. S. (2017). Lopinavir; A Potent Drug against Coronavirus Infection: Insight from Molecular Docking Study. </ref>

== References ==

<references/>

SARS-CoV-2 Coronavirus Main Protease

2020-04-06T15:11:36Z

Gianluca Santoni: Main content of the page created.

I tried to add references in the text (yellow) but I do not know if it will work in proteopedia as I only wrote entrys for Wikimedia.

== Main Protease ==

SARS-CoV-2 is a positive-stranded RNA virus with nucleocapsid which belongs to betacoronaviruses. The 30 kb long +ssRNA contains a 5’-cap structure and a 3’-poly-A tail. After membrane fusion, the viral +ssRNA is released into the cytoplasm and translated into two polyproteins pp1a and pp1ab. <ref> Guo, Y.-R., Cao, Q.-D., Hong, Z.-S., Tan, Y.-Y., Chen, S.-D., Jin, H.-J., Tan, K.-S., Wang, D.-Y. & Yan, Y. (2020). Mil Med Res. 7. </ref> <ref> Cascella, M., Rajnik, M., Cuomo, A., Dulebohn, S. C. & Di Napoli, R. (2020). StatPearls, Vol. p. Treasure Island (FL): StatPearls Publishing. </ref> Papain-like protease(s) and the main protease (also called 3C-like protease [3CLpro]]) are essential for processing the two polyproteins pp1a and pp1ab.
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>

== Overall Structure and Active Centre of 3CLpro ==

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 three domains. 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 catalytic dyad 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.
<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 substrate binding subsite pocket 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 oxyanion hole 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>

== 3CLpro as Potential Drug Target ==

Due to a new outbreak of pulmonary diseases caused by SARS-CoVid-2, the development of new drugs is essential for containment of the viral spread. One promising drug target among coronaviruses is the main protease, as it is essential for processing the polyproteins translated from the viral RNA. Inhibiting this enzyme would block the viral replication and is unlikely to be toxic, as no human proteases with similar cleavage specificity are known. <ref> Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K. & Hilgenfeld, R. (2020). Science. </ref> The potential inhibitor classes can be divided into two classes based on their chemical structures. The first class involves peptide chains that fit the catalytic site of the enzyme by making a covalent link with Cys145, therefore blocking substrate binding. The second class consists of small organic compounds that bind the active site and hence act as competitive inhibitors. Thus, the substrate can not enter the active site cavity. A potential drug which belongs to the second class is Lopinavir, a HIV1 protease inhibitor which seems to be a promising candidate for the treatment of coronavirus infections. <ref> Dayer, M. R., Taleb-Gassabi, S. & Dayer, M. S. (2017). Lopinavir; A Potent Drug against Coronavirus Infection: Insight from Molecular Docking Study. </ref>

== References ==

<references/>

Coronavirus Disease 2019 (COVID-19)

2020-04-06T12:41:50Z

Gianluca Santoni: I've added a session about SARS-CoV2 proteins with solved structures. Links to a page per protein. Included only main protease now.

<SX viewer='molstar' load='' size='340' side='right' caption='Cryo-EM structure of a single spike that consists of 3 chains, colored green, brown and purple (PDB-ID [[6vsb]]).' scene='83/839266/Automatic_colors_occlusion/1'>
[[Image:Ezgif.com-video-to-gif 240px 65pc speed.gif|left|240px|thumb|SARS-CoV-2 virus. The spikes, that adorn the '''virus surface''', impart a '''''corona''''' like appearance [http://www.drugtargetreview.com/news/57287/3d-visualisation-of-covid-19-surface-released-for-researchers (Fusion Animation)].]]

A novel coronavirus, SARS-CoV-2, detected in Wuhan, China in 2019, was found to cause of a respiratory illness, and was named '''''COVID-19'''''.

A [http://youtu.be/hwVl_-lnoys '''''video'''''] (by [http://elarasystems.com Elara Systems)] shows how the virus [http://youtu.be/hwVl_-lnoys '''interacts with its human (host) cell'''], via its spikes (whose 3D structure was determined in the McLellan Lab<ref name="McLellan">PMID:32075877</ref>), thus permitting the viral genome to enter its host & begin infection.

Details of the '''3D structure & function''' of the key proteins & RNA inside the virus can be seen in the NY Times [http://www.nytimes.com/interactive/2020/04/03/science/coronavirus-genome-bad-news-wrapped-in-protein.html '''''Bad News Wrapped in Protein: Inside the Coronavirus Genome'''''].


== Potential treatments for COVID-19 ==
* [http://economictimes.indiatimes.com/news/international/world-news/oxford-university-begins-enrolling-over-500-volunteers-for-coronavirus-vaccine-trial/articleshow/74864754.cms?utm_source=contentofinterest&utm_medium=text&utm_campaign=cppst Oxford Univ begins enrolling over 500 volunteers for a '''coronavirus vaccine trial'''] also see more at [http://www.jenner.ac.uk '''The Jenner Inst'''].

* An international group of scientists (from the UK, Israel & USA) are trying to combat COVID-19 via a massive crystal-based 3D fragment screen. They have determined the 3D structures of [http://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem/Downloads.html '''over 90 fragments, 66 of which are in the active site''']. All the experimental details and results are available [http://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem.html '''online at the Diamond Light Source''']. They welcome contributions in many different forms, see details [http://covid.postera.ai/covid '''PostEra'''].

* 31-Mar-2020 ''NY Times'' [http://www.nytimes.com/2020/03/31/health/cdc-masks-coronavirus.html C.D.C. Weighs Advising Everyone to Wear a Mask].

* 27-Mar-2020 ''Science'' - Not wearing masks to protect against coronavirus is a '''big mistake''', top Chinese scientist, Dr. George Gao, Director General of the Chinese CDC says, as reported in [http://www.sciencemag.org/news/2020/03/not-wearing-masks-protect-against-coronavirus-big-mistake-top-chinese-scientist-says ''Science''].

* 23-Mar-2020 ''NY Times'' - A USA, French UK study '''identified 69 drugs to test against the coronavirus'''<ref> Gordon, et al. A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing: bioRxiv (online) 2020 [http://doi.org/10.1101/2020.03.22.002386 http://doi.org/10.1101/2020.03.22.002386]</ref>. As reported in the [http://www.nytimes.com/2020/03/22/science/coronavirus-drugs-chloroquine.html?action=click&module=Top%20Stories&pgtype=Homepage ''New York Times''] "The researchers sought drugs that also latch onto the human proteins that the coronavirus seems to need to enter and replicate in human cells."

* 20-Mar-2020 - Analysis by Abby Olena in ''The Scientist'' on [http://www.the-scientist.com/news-opinion/remdesivir-works-great-against-coronaviruses-in-the-lab-67298?utm_campaign=TS_OTC_2020&utm_source=hs_email&utm_medium=email&utm_content=85306117&_hsenc=p2ANqtz--t49MmUS_nL_8CL8wosEbymFBDq_4smPhI1pSJmSKWA0bURCpjoMb1eYxIVv30SDzsuiNd9PRGTPC30x-gelTGjK-9r9wPWaMjEZIqjaz5Y0tgW5w&_hsmi=85306117 '''Remdesivir Works Against Coronaviruses in the Lab''']

* 20-Mar-2020 - Analysis by Chris Baraniuk in ''The Scientist'' on [http://www.the-scientist.com/news-opinion/is-hype-over-chloroquine-as-a-potential-covid-19-therapy-justified--67301?utm_campaign=TS_OTC_2020&utm_source=hs_email&utm_medium=email&utm_content=85306117&_hsenc=p2ANqtz--t49MmUS_nL_8CL8wosEbymFBDq_4smPhI1pSJmSKWA0bURCpjoMb1eYxIVv30SDzsuiNd9PRGTPC30x-gelTGjK-9r9wPWaMjEZIqjaz5Y0tgW5w&_hsmi=85306117 '''Chloroquine for COVID-19: Cutting Through the Hype''']

* A French study<ref> Gautret, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open- label non-randomized clinical trial: Intl J Antimcrob Agents (in press) 2020 [http://dx.doi.org/10.1016/j.ijantimicag.2020.105949 http://dx.doi.org/10.1016/j.ijantimicag.2020.105949]</ref> showed, despite its small sample size (20 patients treated), that '''hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients''' and its effect is reinforced by azithromycin.

== Videos helping to explain COVID-19 ==
<html5media height="160" width="400">https://w.soundcloud.com/player/?url=https%3A//api.soundcloud.com/tracks/775538998&color=%23ff5500&auto_play=false&hide_related=false&show_comments=true&show_user=true&show_reposts=false&show_teaser=true</html5media> 
Scientists have turned the coronavirus spike protein structure into '''music(!!)''', as reported in [http://www.sciencemag.org/news/2020/04/scientists-have-turned-structure-coronavirus-music?fbclid=IwAR0-kIT3mVjRHe18Y7wf3KrqaBIvIk9JGG9KuJsbA0zN6gsov0Np0p_jO9A# ''Science''] by [http://soundcloud.com/user-275864738/viral-counterpoint-of-the-coronavirus-spike-protein-2019-ncov Soundcloud]. 
 
<html5media height="225" width="400">http://www.youtube.com/watch?v=HhNo_IOPOtU</html5media> 
The Czech Republic took the uncommon step of '''making wearing of masks mandatory in public spaces''', prompting a grassroots [http://www.sciencemag.org/news/2020/03/would-everyone-wearing-face-masks-help-us-slow-pandemicdrive effort to make & wear masks]. '''The impact has been extraordinary!!''' 
 
<html5media height="225" width="400">http://www.youtube.com/watch?v=hm7BmIJrLZE</html5media> 
Japan researchers show how '''Coronavirus spreads through micro droplets'''. These tiny droplets containing the virus can stay in the air for extended periods. 
 
<html5media height="225" width="400">http://www.youtube.com/watch?v=qzARpgx8cvE</html5media> 
Speaking face-to-face is exchanging saliva, so '''stop speaking face-to-face and stay healthy''' by [http://stoptheviruscovid19.github.io '''stoptheviruscovid''']. 
 
<html5media height="225" width="400">http://www.youtube.com/watch?v=Kas0tIxDvrg</html5media> 
Modeling an epidemic (6-Mar-2020) '''''We're not ready for the next epidemic''''' by [http://3b1b.co/covid-thanks '''3blue1brown''']. 
 
<html5media height="225" width="400">https://www.youtube.com/watch?v=s2EVlqql_f8</html5media> 
'''Fighting Coronavirus with Soap''' by [http://pdb101.rcsb.org/ '''PDB-101''']. 
 
<html5media height="225" width="400">https://www.youtube.com/watch?v=I0TmBsHaGmI</html5media> 
'''Background about the Coronavirus-COVID-19 and details of its 3D structure''' by [http://www.biolution.net biolution '''GmBH''']. 
 
<html5media height="225" width="400">https://www.youtube.com/watch?v=I-Yd-_XIWJg</html5media> 
'''Outbreak of COVID-19 explained through 3D Medical Animation (Feb 11, 2020)''' by [http://www.scientificanimations.com '''Sci Animations''']. 
 
<html5media height="225" width="400">http://www.youtube.com/watch?v=6Af6b_wyiwI</html5media> 
'''Bill Gates Ted Talk (3-Apr-2015) ''We're not ready for the next epidemic''''' by [http://www.ted.com/talks '''Ted Talks'''].
 
<html5media height="225" width="400">https://www.youtube.com/watch?v=B00tJnbktVo&feature=youtu.be&t=210</html5media> 
'''Jürgen Bosch Presentation (31-Mar-2020) ''Coronavirus: How it Ticks and What we are Doing to Stop it''''' by [http://www.linkedin.com/in/jubosch '''Jürgen Bosch'''].

== Useful sites on COVID-19 ==
* [http://deepmind.com/research/open-source/computational-predictions-of-protein-structures-associated-with-COVID-19 Computational predictions of 3D protein structures associated with COVID-19] based on the [http://deepmind.com/blog/article/AlphaFold-Using-AI-for-scientific-discovery AI AlphaFold system]. Coordinates of the 3D structures can be download [http://storage.googleapis.com/deepmind-com-v3-datasets/alphafold-covid19/structures_4_3_2020.zip here as a '''zip''' file].

* Up to date statistics on [http://www.worldometers.info/coronavirus/coronavirus-cases/ Coronavirus cases world-wide at worldometer]

* A summary of key findings about [http://www.cdc.gov/coronavirus/2019-nCoV/lab/index.html COVID-19] can be found at [http://www.cdc.gov/ CDC].

* '''Coronavirus Evolved Naturally''', and ‘Is '''Not''' a Laboratory Construct,’ in a study in Nature Med by Anderson and colleagues <ref>Andersen, et al. The proximal origin of SARS-CoV-2: Nature Med (in press) 2020 [http://dx.doi.org/10.1038/s41591-020-0820-9 http://dx.doi.org/10.1038/s41591-020-0820-9]]</ref>.

* '''Scientists are endeavoring to find antivirals specific to the virus'''. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of COVID-19 in China, with some promising results summarized.<ref>PMID:32147628</ref>.

* [http://crowdfightcovid19.org Crowdfight COVID-19] - A scientific crowdsourcing initiative to put all available resources at the service of the fight against COVID-19

* A computer game, developed at the [http://www.ipd.uw.edu Inst for Protein Design] (U Washington), uses crowdsourcing to try to find new lead compound that might become drugs to treat COVID-19.
<html5media height="225" width="400" >https://www.youtube.com/watch?v=gGvlNo3nMfw</html5media>

== SARS-CoV-2 virus proteins ==
The genome of the SARS-CoV-2 virus codes for 28 proteins:
Out of those, 19 have already been characterized structurally.

* [[SARS-CoV-2 Coronavirus Main Protease| Main protease]]: it is a cysteine protease that is essential for the viral life cycle.

== 3D structural studies on SARS-CoV-2 virus==

* A team of UK & Israeli scientists determined the 3D structures of [http://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem/Downloads.html '''over 90 fragments, 66 of which are in the active site'']. All the experimental details and results are available [http://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem.html '''online at the Diamond Light Source'''].

* A team of Chinese scientists determined, by Cryo-EM, the''' coronavirus spike receptor-binding domain complexed with its receptor ACE2 PDB-ID''' [http://www.rcsb.org/structure/6LZG 6LZG]. (To be published).

* A team of US and Chinese scientists determined the crystal structure of '''2019-nCoV spike receptor-binding domain bound with ACE2''' [http://www.rcsb.org/structure/6M0J 6M0J] (To be published).

* A team of US scientists determined, by Cryo-EM, the '''structure of the SARS-CoV-2 spike glycoprotein (open & closed states)''' <ref>PMID:32155444</ref>, PDB-ID [http://www.rcsb.org/structure/6VXX 6VXX] & [http://www.rcsb.org/structure/6VYB 6VYB]

* Crystal structure of SARS-CoV-2 receptor binding domain in complex with human antibody CR3022 [http://www.rcsb.org/structure/6W41 6W41] (To be published).

* Crystal Structure of the methyltransferase-stimulatory factor complex of NSP16 and NSP10 from SARS CoV-2 [http://www.rcsb.org/structure/6W61 6W61] (To be published).

* Crystal Structure of ADP ribose phosphatase of NSP3 from SARS CoV-2 in complex with AMP [http://www.rcsb.org/structure/6W6Y 6W6Y] (To be published).

* Structure of NSP10 - NSP16 Complex from SARS-CoV-2 [http://www.rcsb.org/structure/6W75 6W75] (To be published).

* Crystal structure of SARS-CoV-2 nucleocapsid protein N-terminal RNA binding domain [http://www.rcsb.org/structure/6M3M 6M3M] (To be published).

* Crystal structure of Nsp9 RNA binding protein of SARS CoV-2 [http://www.rcsb.org/structure/6W4B 6W4B] (To be published).

* Crystal Structure of NSP16 - NSP10 Complex from SARS-CoV-2 [http://www.rcsb.org/structure/6W4H 6W4H] (To be published).

* Cryo-EM structure of the 2019-nCoV RBD/ACE2-B0AT1 complex<ref>PMID:32132184</ref> [http://www.rcsb.org/structure/6M17 6M17].

* Crystal structure of RNA binding domain of nucleocapsid phosphoprotein from SARS coronavirus 2 [http://www.rcsb.org/structure/6VYO 6VYO] (To be published).

* Crystal structure of NSP15 Endoribonuclease from SARS CoV-2 in the Complex with a Citrate [http://www.rcsb.org/structure/6W01 6W01] (To be published).

* Crystal structure of ADP ribose phosphatase of NSP3 from SARS CoV-2 in the complex with ADP ribose [http://www.rcsb.org/structure/6W02 6W02] (To be published).

* Crystal structure of 2019-nCoV chimeric receptor-binding domain complexed with its receptor human ACE2 [http://www.rcsb.org/structure/6VW1 6VW1] (To be published).

* Crystal structure of NSP15 Endoribonuclease from SARS CoV-2 [http://www.rcsb.org/structure/6VWW 6VWW] (To be published).

* Crystal Structure of ADP ribose phosphatase of NSP3 from SARS CoV-2 [http://www.rcsb.org/structure/6VXS 6VXS] (To be published).

* Crystal structure of the 2019-nCoV HR2 Domain [http://www.rcsb.org/structure/6LVN 6LVN] (To be published).

* Crystal structure of post fusion core of 2019-nCoV S2 subunit [http://www.rcsb.org/structure/6LXT 6LXT] (To be published).

* Crystal structure of '''SARS-CoV-2 main protease''' provides a basis for design of improved α-ketoamide inhibitors, from the Hilgenfeld lab<ref>PMID:32198291</ref>, Apo Struture: PDB-ID [http://www.rcsb.org/structure/6y2e 6Y2E], and complexes with inhibitors: PDB-ID [http://www.rcsb.org/structure/6y2f 6Y2F] and [http://www.rcsb.org/structure/6y2g 6Y2G].

* 3D Structure of '''RNA-dependent RNA polymerase from COVID-19''', a '''major antiviral drug target''' from the Rao lab in Beijing<ref> Gao, et al. Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target: bioRxiv (online) 2020 [https://doi.org/10.1101/2020.03.16.993386 https://doi.org/10.1101/2020.03.16.993386]</ref>.

* Crystal structure of the '''Mpro from COVID-19''' and '''discovery of inhibitors''' in a study by scientists from Shanghai & Beijing <ref> Jin, et al. Structure of Mpro from COVID-19 virus and discovery of its inhibitors: bioRxiv (online) 2020 [http://doi.org/10.1101/2020.02.26.964882 http://doi.org/10.1101/2020.02.26.964882]</ref>, PDB-ID [[2h2z]].

* Crystal structure of '''Nsp15 endoribonuclease NendoU from SARS-CoV-2''' in a study by scientists from USA<ref> Kim, et al. Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2: bioRxiv (online) 2020 [http://doi.org/10.1101/2020.03.02.968388 http://doi.org/10.1101/2020.03.02.968388]</ref>, PDB-ID [[6w01]].

* A study by Zhou & colleagues on the structural basis for the '''recognition of the SARS-CoV-2 (COVID-19) by full-length human ACE2''' gives insights to the molecular basis for coronavirus recognition and infection<ref>PMID:32132184</ref>.

* '''The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics'''. A study by McLellan and colleagues in "Science" on the Cryo-EM structure of the COVID-19 spike protein. This structure should greatly aid in the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis<ref name="McLellan" />, PDB-ID [[6vsb]].

* [http://github.com/thorn-lab/coronavirus_structural_task_force Public resource for the structures from beta-coronavirus with a focus on SARS-CoV and SARS-CoV-2]

== References ==
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[[Category: Coronavirus]]
[[Category: Covid-19]]