SARS Coronavirus Main Proteinase - Revision history

Ann Taylor at 19:33, 20 February 2023

Ann Taylor — Mon, 20 Feb 2023 19:33:05 GMT

←Older revision		Revision as of 19:33, 20 February 2023
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	Each monomer of the SARS M<sup>pro</sup> consists of three domains. The two monomers are arranged perpendicular to each other and the active site is located at the connection between the first <scene name='SARS_Coronavirus_Main_Proteinase/Domains_1-3/1'>domain</scene> (residues 1-101) and second domain (residues 102-184). The catalytic dyad is composed of Histidine 41 and Cysteine 145. From the pH dependency of enzymatic activity, the pKa's have been determined as 6.4 for the histidine and 8.3 for the cysteine. The cysteine acts as the nucleophile in the proteolytic cleavage reaction. <ref>Anad, K., Ziebhr, J., Wadhani, P., Mesters, J.R., and Hilgenfeld, R. (2003). Coronavirus main protease (3CLPro) structure: basis for design of anti-SARS drugs. Science300, 1763-1767.</ref>		Each monomer of the SARS M<sup>pro</sup> consists of three domains. The two monomers are arranged perpendicular to each other and the active site is located at the connection between the first <scene name='SARS_Coronavirus_Main_Proteinase/Domains_1-3/1'>domain</scene> (residues 1-101) and second domain (residues 102-184). The catalytic dyad is composed of Histidine 41 and Cysteine 145. From the pH dependency of enzymatic activity, the pKa's have been determined as 6.4 for the histidine and 8.3 for the cysteine. The cysteine acts as the nucleophile in the proteolytic cleavage reaction. <ref>Anad, K., Ziebhr, J., Wadhani, P., Mesters, J.R., and Hilgenfeld, R. (2003). Coronavirus main protease (3CLPro) structure: basis for design of anti-SARS drugs. Science300, 1763-1767.</ref>
		+
		+	==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.

	==Mechanism of Inactivation by Benzotriazole Esters==		==Mechanism of Inactivation by Benzotriazole Esters==

Ann Taylor at 04:54, 19 February 2023

Ann Taylor — Sun, 19 Feb 2023 04:54:06 GMT

←Older revision		Revision as of 04:54, 19 February 2023
Line 1:		Line 1:
	<StructureSection load='2vj1' size='350' side='right' caption='Human SARS coronavirus proteinase dimer complex with benzoic acid, dimethylamino benzoic acid and DMSO, [[2vj1]]' scene=''>		<StructureSection load='2vj1' size='350' side='right' caption='Human SARS coronavirus proteinase dimer complex with benzoic acid, dimethylamino benzoic acid and DMSO, [[2vj1]]' scene=''>
	==Introduction==		==Introduction==
-	Before the emergence of the SARS-CoV, no research efforts were being directed toward the discovery of antiviral drugs against coronaviruses. The high infectivity and mortality rate established SARS as a significant global threat for which no efficacious therapy was available. Since the epidemic, which began in 2003, new insights into the genomics and pathogenisis of the SARS-CoV revealed several novel potential anti-coronavirus targets. Several proteins encoded by the SARS-CoV could be considered as targets for therapeutic intervention. The focus of this article is the '''SARS-CoV main protease'''. ~~Norovirus~~ protease is an essential enzyme for proteoplytic maturation of ~~norovirus~~ nonstructural proteins and is implicated as a potential antiviral drug target<ref>PMID:23319456</ref>.	+	Before the emergence of the SARS-CoV, no research efforts were being directed toward the discovery of antiviral drugs against coronaviruses. The high infectivity and mortality rate established SARS as a significant global threat for which no efficacious therapy was available. Since the epidemic, which began in 2003, new insights into the genomics and pathogenisis of the SARS-CoV revealed several novel potential anti-coronavirus targets. Several proteins encoded by the SARS-CoV could be considered as targets for therapeutic intervention. The focus of this article is the '''SARS-CoV main protease'''. This protease is an essential enzyme for proteoplytic maturation of nonstructural proteins and is implicated as a potential antiviral drug target<ref>PMID:23319456</ref>.

	==Coronaviruses==		==Coronaviruses==
	[[Image:SARS.jpg\|left\|250px]]		[[Image:SARS.jpg\|left\|250px]]
	{{Clear}}		{{Clear}}
-	Coronaviruses are enveloped, positive-sense RNA viruses and are the second most prevalent cause of the common cold (rhinoviruses are the first). These viruses have the longest non-segmented RNA genomes currently known, ranging from 27 to 31 kb. Translation of the genome occurs in two phases: (1) the early phase ~~were~~ the viral replicase complex is assembled, and (2) the late phase, structural and nonstructural proteins are translated from a negative-sense RNA template. <ref>Murray, Patrick R., Ken S. Rosenthal, and Michael A. Pfaller. "Coronaviruses and Noroviruses." Medical Microbiology. 6th ed. Philadelphia: Mosby/Elsevier, 2009. 565-68. Print.</ref> The maturation of the RNA polymerase is achieved through extensive proteolytic processing by three cysteine peptidases. Two are papain-like proteases (PL<sup>pro</sup>) and the third is the main protease, also known as the 3C-like protease (3Cl<sup>pro</sup>). <ref>Ziebuhr, J., Herold,J., and Siddell, S.G. (1995). Characterization of a human coronavirus (strain 229E) 3C-like proteinase activity. J. Virol. 69, 4331-4338.</ref>	+	Coronaviruses are enveloped, positive-sense RNA viruses and are the second most prevalent cause of the common cold (rhinoviruses are the first). These viruses have the longest non-segmented RNA genomes currently known, ranging from 27 to 31 kb. Translation of the genome occurs in two phases: (1) the early phase where the viral replicase complex is assembled, and (2) the late phase, structural and nonstructural proteins are translated from a negative-sense RNA template. <ref>Murray, Patrick R., Ken S. Rosenthal, and Michael A. Pfaller. "Coronaviruses and Noroviruses." Medical Microbiology. 6th ed. Philadelphia: Mosby/Elsevier, 2009. 565-68. Print.</ref> The maturation of the RNA polymerase is achieved through extensive proteolytic processing by three cysteine peptidases. Two are papain-like proteases (PL<sup>pro</sup>) and the third is the main protease, also known as the 3C-like protease (3Cl<sup>pro</sup>). <ref>Ziebuhr, J., Herold,J., and Siddell, S.G. (1995). Characterization of a human coronavirus (strain 229E) 3C-like proteinase activity. J. Virol. 69, 4331-4338.</ref>
	{{clear}}		{{clear}}
	==SARS==		==SARS==
	[[Image:SARS_masks.jpg\|left\|200px]]		[[Image:SARS_masks.jpg\|left\|200px]]
	{{Clear}}		{{Clear}}
-	The highly infectious severe acute respiratory syndrome (SARS) has caused one near pandemic to date, between the months of November 2002 and July 2003, with 8,096 known cases and 774 confirmed deaths (a fatality rate of nearly 10%). Genetic comparisons revealed this virus as a completely new coronavirus. <ref>Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003;348:1953-1966</ref> According to the World Health Organization's (WHO) April 2004 concluding report, China had the vast majority of cases, but Taiwan, Singapore, and Canada also had cases in the hundreds. <ref>"Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003". WHO. Retrieved 2008-10-31.</ref> The virus spread to 37 countries, but the Global Alert and Response system as well as drastic action taken by the Chinese government effectively limited the spread of the disease. It has been established that the SARS virus can infect birds, livestock, and pets~~; however, the exact reservoir and range of host species is, at this point, unknown and SARS has the potential to reemerge at an unknown time~~. <ref>Li W, Shi Z, Yu M, et al. (2005). "Bats are natural reservoirs of SARS-like coronaviruses". Science (journal) 310 (5748): 676–9. doi:10.1126/science.1118391. PMID 16195424.</ref>	+	The highly infectious severe acute respiratory syndrome (SARS) has caused one near pandemic to date, between the months of November 2002 and July 2003, with 8,096 known cases and 774 confirmed deaths (a fatality rate of nearly 10%). Genetic comparisons revealed this virus as a completely new coronavirus. <ref>Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003;348:1953-1966</ref> According to the World Health Organization's (WHO) April 2004 concluding report, China had the vast majority of cases, but Taiwan, Singapore, and Canada also had cases in the hundreds. <ref>"Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003". WHO. Retrieved 2008-10-31.</ref> The virus spread to 37 countries, but the Global Alert and Response system as well as drastic action taken by the Chinese government effectively limited the spread of the disease. It has been established that the SARS virus can infect birds, livestock, and pets. <ref>Li W, Shi Z, Yu M, et al. (2005). "Bats are natural reservoirs of SARS-like coronaviruses". Science (journal) 310 (5748): 676–9. doi:10.1126/science.1118391. PMID 16195424.</ref> The re-emergence of SARS-CoV2 in late 2019/early 2020 led to a global pandemic <ref>PMID:33572857</ref>.
	{{clear}}		{{clear}}
	==The SARS Main Protease==		==The SARS Main Protease==

Alexander Berchansky at 11:25, 24 January 2021

Alexander Berchansky — Sun, 24 Jan 2021 11:25:33 GMT

←Older revision		Revision as of 11:25, 24 January 2021
Line 4:		Line 4:

	==Coronaviruses==		==Coronaviruses==
-	[[Image:SARS.jpg\|left\|250px]]Coronaviruses are enveloped, positive-sense RNA viruses and are the second most prevalent cause of the common cold (rhinoviruses are the first). These viruses have the longest non-segmented RNA genomes currently known, ranging from 27 to 31 kb. Translation of the genome occurs in two phases: (1) the early phase were the viral replicase complex is assembled, and (2) the late phase, structural and nonstructural proteins are translated from a negative-sense RNA template. <ref>Murray, Patrick R., Ken S. Rosenthal, and Michael A. Pfaller. "Coronaviruses and Noroviruses." Medical Microbiology. 6th ed. Philadelphia: Mosby/Elsevier, 2009. 565-68. Print.</ref> The maturation of the RNA polymerase is achieved through extensive proteolytic processing by three cysteine peptidases. Two are papain-like proteases (PL<sup>pro</sup>) and the third is the main protease, also known as the 3C-like protease (3Cl<sup>pro</sup>). <ref>Ziebuhr, J., Herold,J., and Siddell, S.G. (1995). Characterization of a human coronavirus (strain 229E) 3C-like proteinase activity. J. Virol. 69, 4331-4338.</ref>	+	[[Image:SARS.jpg\|left\|250px]]
		+	{{Clear}}
		+	Coronaviruses are enveloped, positive-sense RNA viruses and are the second most prevalent cause of the common cold (rhinoviruses are the first). These viruses have the longest non-segmented RNA genomes currently known, ranging from 27 to 31 kb. Translation of the genome occurs in two phases: (1) the early phase were the viral replicase complex is assembled, and (2) the late phase, structural and nonstructural proteins are translated from a negative-sense RNA template. <ref>Murray, Patrick R., Ken S. Rosenthal, and Michael A. Pfaller. "Coronaviruses and Noroviruses." Medical Microbiology. 6th ed. Philadelphia: Mosby/Elsevier, 2009. 565-68. Print.</ref> The maturation of the RNA polymerase is achieved through extensive proteolytic processing by three cysteine peptidases. Two are papain-like proteases (PL<sup>pro</sup>) and the third is the main protease, also known as the 3C-like protease (3Cl<sup>pro</sup>). <ref>Ziebuhr, J., Herold,J., and Siddell, S.G. (1995). Characterization of a human coronavirus (strain 229E) 3C-like proteinase activity. J. Virol. 69, 4331-4338.</ref>
	{{clear}}		{{clear}}
	==SARS==		==SARS==
-	[[Image:SARS_masks.jpg\|left\|200px]]The highly infectious severe acute respiratory syndrome (SARS) has caused one near pandemic to date, between the months of November 2002 and July 2003, with 8,096 known cases and 774 confirmed deaths (a fatality rate of nearly 10%). Genetic comparisons revealed this virus as a completely new coronavirus. <ref>Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003;348:1953-1966</ref> According to the World Health Organization's (WHO) April 2004 concluding report, China had the vast majority of cases, but Taiwan, Singapore, and Canada also had cases in the hundreds. <ref>"Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003". WHO. Retrieved 2008-10-31.</ref> The virus spread to 37 countries, but the Global Alert and Response system as well as drastic action taken by the Chinese government effectively limited the spread of the disease. It has been established that the SARS virus can infect birds, livestock, and pets; however, the exact reservoir and range of host species is, at this point, unknown and SARS has the potential to reemerge at an unknown time. <ref>Li W, Shi Z, Yu M, et al. (2005). "Bats are natural reservoirs of SARS-like coronaviruses". Science (journal) 310 (5748): 676–9. doi:10.1126/science.1118391. PMID 16195424.</ref>	+	[[Image:SARS_masks.jpg\|left\|200px]]
		+	{{Clear}}
		+	The highly infectious severe acute respiratory syndrome (SARS) has caused one near pandemic to date, between the months of November 2002 and July 2003, with 8,096 known cases and 774 confirmed deaths (a fatality rate of nearly 10%). Genetic comparisons revealed this virus as a completely new coronavirus. <ref>Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003;348:1953-1966</ref> According to the World Health Organization's (WHO) April 2004 concluding report, China had the vast majority of cases, but Taiwan, Singapore, and Canada also had cases in the hundreds. <ref>"Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003". WHO. Retrieved 2008-10-31.</ref> The virus spread to 37 countries, but the Global Alert and Response system as well as drastic action taken by the Chinese government effectively limited the spread of the disease. It has been established that the SARS virus can infect birds, livestock, and pets; however, the exact reservoir and range of host species is, at this point, unknown and SARS has the potential to reemerge at an unknown time. <ref>Li W, Shi Z, Yu M, et al. (2005). "Bats are natural reservoirs of SARS-like coronaviruses". Science (journal) 310 (5748): 676–9. doi:10.1126/science.1118391. PMID 16195424.</ref>
	{{clear}}		{{clear}}
	==The SARS Main Protease==		==The SARS Main Protease==
-	[[Image:Picture 4.png\|right\|250px]]Development of broad spectrum antivirals for coronaviruses is highly desirable as several new species have been recently discovered and the coronaviruses tend to have a wide host range . Thus the highly conserved M<sup>pro</sup> is an ideal target for viral inhibition. The M<sup>pro</sup> is necessary for cleaving at least 11 conserved sites containing a large hydrophobic residue (preferably Leu) in P2, a Gln in the P1 position, and a small aliphatic aa residue (Ser,Gly,Ala) in the P1’ position. <ref>Ziebuhr, J., Snijder, E.J., and Gorbaleya, A.E. (2000). Virus-encoded proteinases and proteolytic processing in Nidovirales. J. Gen. Virol. 81, 853-879.</ref>	+	[[Image:Picture 4.png\|right\|250px]]
		+	{{Clear}}
		+	Development of broad spectrum antivirals for coronaviruses is highly desirable as several new species have been recently discovered and the coronaviruses tend to have a wide host range . Thus the highly conserved M<sup>pro</sup> is an ideal target for viral inhibition. The M<sup>pro</sup> is necessary for cleaving at least 11 conserved sites containing a large hydrophobic residue (preferably Leu) in P2, a Gln in the P1 position, and a small aliphatic aa residue (Ser,Gly,Ala) in the P1’ position. <ref>Ziebuhr, J., Snijder, E.J., and Gorbaleya, A.E. (2000). Virus-encoded proteinases and proteolytic processing in Nidovirales. J. Gen. Virol. 81, 853-879.</ref>

	The SARS main protease, M<sup>pro</sup>, is a 33.8 kDA protein belonging to the cysteine protease family. As in all coronaviruses, except infectious bronchitis virus (IBV), the enzyme is a homodimer. <ref>Anad, K., Ziebhr, J., Wadhani, P., Mesters, J.R., and Hilgenfeld, R. (2003). Coronavirus main protease (3CLPro) structure: basis for design of anti-SARS drugs. Science300, 1763-1767.</ref> It has been established that dimerization is essential for catalytic activity because the N-finger of one subunit is involved in organizing the substrate binding-pocket of the other. Furthermore, deletion of the N-finger also results in the inability of the monomers to dimerize.		The SARS main protease, M<sup>pro</sup>, is a 33.8 kDA protein belonging to the cysteine protease family. As in all coronaviruses, except infectious bronchitis virus (IBV), the enzyme is a homodimer. <ref>Anad, K., Ziebhr, J., Wadhani, P., Mesters, J.R., and Hilgenfeld, R. (2003). Coronavirus main protease (3CLPro) structure: basis for design of anti-SARS drugs. Science300, 1763-1767.</ref> It has been established that dimerization is essential for catalytic activity because the N-finger of one subunit is involved in organizing the substrate binding-pocket of the other. Furthermore, deletion of the N-finger also results in the inability of the monomers to dimerize.
Line 17:		Line 23:

	==Mechanism of Inactivation by Benzotriazole Esters==		==Mechanism of Inactivation by Benzotriazole Esters==
-	[[Image:Picture_6.png\|right\|250px]]A number of peptidic inhibitors have been derived from substrate cleavage consensus sequences, but until recently there have been only a small number of nonpeptidic inhibitors reported. Rather serendipitously, it was noticed that the intermediate benzotriazole esters, occurring during the synthesis of HIV proteinase inhibitors, were better inhibitors of the SARS M<sup>pro</sup> than the end products themselves. These inhibitors have a reported K<sub>i</sub> of 7.5 nM, among the highest levels of inhibition described so far. Spectrometric analyses suggested that the benzotriazole are mechanism based inhibitors which irreversibly acylate the active-site Cys145. Better visualization of the binding mode was observed through x-ray crystallography of the enzyme incubated with two benzotriazole ester compounds: 1-(benzoyloxy)-benzotriazole (compound XP-27) and 1-(4-dimethylaminobenzoyloxy)-benzotriazole (compound XP-59). Kinetic analysis found that XP-59 was more stable, and unlike XP-27, it showed a normal hyperbolic inhibition curve. XP-59 and its covalent M<sup>pro</sup> product were more stable due to the electron donating nature of the p-dimethylamino group, which reduces the electrophilicity of the carbonyl carbon compared to XP-27. Addition of XP-27 to the enzyme led to rapid inactivation, however, after a few minutes the enzyme activity began to recover due to the instability of the thioester product. <ref>Verschueren, Koen H.G., Ksenia Pumpor, Stefan Anemüller, Shuai Chen, Jeroen R. Mesters, and Rolf Hilgenfeld. "A Structural View of the Inactivation of the SARS Coronavirus Main Proteinase by Benzotriazole Esters." Chemistry & Biology 15.6 (2008): 597-606. Web. Oct. 2010.</ref>	+	[[Image:Picture_6.png\|right\|250px]]
		+	{{Clear}}
		+	A number of peptidic inhibitors have been derived from substrate cleavage consensus sequences, but until recently there have been only a small number of nonpeptidic inhibitors reported. Rather serendipitously, it was noticed that the intermediate benzotriazole esters, occurring during the synthesis of HIV proteinase inhibitors, were better inhibitors of the SARS M<sup>pro</sup> than the end products themselves. These inhibitors have a reported K<sub>i</sub> of 7.5 nM, among the highest levels of inhibition described so far. Spectrometric analyses suggested that the benzotriazole are mechanism based inhibitors which irreversibly acylate the active-site Cys145. Better visualization of the binding mode was observed through x-ray crystallography of the enzyme incubated with two benzotriazole ester compounds: 1-(benzoyloxy)-benzotriazole (compound XP-27) and 1-(4-dimethylaminobenzoyloxy)-benzotriazole (compound XP-59). Kinetic analysis found that XP-59 was more stable, and unlike XP-27, it showed a normal hyperbolic inhibition curve. XP-59 and its covalent M<sup>pro</sup> product were more stable due to the electron donating nature of the p-dimethylamino group, which reduces the electrophilicity of the carbonyl carbon compared to XP-27. Addition of XP-27 to the enzyme led to rapid inactivation, however, after a few minutes the enzyme activity began to recover due to the instability of the thioester product. <ref>Verschueren, Koen H.G., Ksenia Pumpor, Stefan Anemüller, Shuai Chen, Jeroen R. Mesters, and Rolf Hilgenfeld. "A Structural View of the Inactivation of the SARS Coronavirus Main Proteinase by Benzotriazole Esters." Chemistry & Biology 15.6 (2008): 597-606. Web. Oct. 2010.</ref>

Michal Harel at 07:18, 29 October 2020

Michal Harel — Thu, 29 Oct 2020 07:18:51 GMT

←Older revision		Revision as of 07:18, 29 October 2020
Line 27:		Line 27:
	==3D structures of virus proteinase==		==3D structures of virus proteinase==

-	See [[Virus ~~proteases~~ 3D structures]]	+	See [[Virus protease 3D structures]]

	==References==		==References==
	{{reflist}}		{{reflist}}
	[[Category:Topic Page]]		[[Category:Topic Page]]

Michal Harel at 09:15, 28 October 2020

Michal Harel — Wed, 28 Oct 2020 09:15:36 GMT

←Older revision		Revision as of 09:15, 28 October 2020
Line 27:		Line 27:
	==3D structures of virus proteinase==		==3D structures of virus proteinase==

-	~~Updated on {{REVISIONDAY2}}-{{MONTHNAME\|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}~~	+	See [[Virus proteases 3D structures]]
-	~~{{#tree:id=OrganizedByTopic\|openlevels=0\|~~	+

-	*Coronavirus 3C-like proteinase residues 3248-3553
-
-	**[[1q2w]], [[3iwm]], [[3ebn]], [[3d23]], [[5b6o]], [[2gt7]], [[1z1i]], [[2a5a]], [[2c3s]], [[2bx3]], [[2bx4]], [[1uj1]], [[1uk2]], [[1uk3]], [[2duc]], [[2yna]], [[5c3n]] – 3CLP - SARS coronavirus<br />
-	**[[2liz]] – 3CLP – NMR<br />
-	**[[4ylu]], [[4wy3]], [[5c5n]], [[5c5o]], [[4tww]], [[4twy]], [[4zro]], [[2amd]], [[2amq]], [[2amp]], [[1wof]], [[2ynb]], [[3d62]], [[2d2d]] – 3CLP + inhibitor <br />
-	**[[3atw]], [[3avz]] – 3CLP (mutant) + inhibitor <br />
-	**[[2vj1]], [[3tit]], [[3tiu]] – 3CLP + unsaturated ester<br />
-	**[[3m3s]], [[3m3t]], [[3m3v]], [[3fzd]], [[3f9e]], [[3f9f]], [[3f9g]], [[3f9h]], [[3ea7]], [[3ea8]], [[3ea9]], [[3eaj]], [[3e91]], [[3ee7]], [[2qc2]], [[2qcy]], [[2pwx]], [[2gt8]], [[1z1j]], [[3aw1]], [[4wmd]], [[4wme]], [[4wmf]], [[5b6o]] – 3CLP (mutant) <br />
-	**[[2zu2]], [[2zu4]], [[2zu5]], [[3tns]], [[3tnt]], [[3aw0]] – 3CLP + peptidomimetic compound<br />
-	**[[2z9g]] – 3CLP + benzene + Hg<br />
-	**[[2z9j]], [[2z9k]], [[2z9l]] – 3CLP + Zn compound<br />
-	**[[2z3c]], [[2z3d]], [[2z3e]], [[2gx4]], [[1uk4]] – 3CLP + peptide inhibitor <br />
-	**[[2gtb]] - 3CLP (mutant) + aza-peptide epoxide inhibitor <br />
-	**[[2a5i]], [[2a5k]] - 3CLP + aza-peptide epoxide inhibitor <br />
-
-	*Coronavirus papain-like proteinase residues 1481-1811
-
-	**[[4rez]], [[4rna]], [[5ko3]] – 3CLP <br />
-	**[[4r3d]], [[4rsp]] – 3CLP + inhibitor <br />
-	**[[4rf0]], [[4rf1]] – 3CLP + ubiquitin/RPL40 <br />
-	**[[5v69]], [[5v6a]] – 3CLP + ubiquitin <br />
-	**[[5tl6]], [[5tl7]] – 3CLP + ubiquitin-like protein C-terminal <br />
-	**[[4wur]] – 3CLP (mutant) + ubiquitin <br />
-
-	*Coronavirus other regions
-
-	**[[5gwy]] – 3CLP residues 2940-3242 + inhibitor <br />
-	**[[5hih]] – 3CLP residues 1109-1275 <br />
-
-	*Norovirus 3C-like (or Norwalk) protease residues 1101-1281
-
-	**[[2fyq]], [[3ur6]], [[2fyr]] – 3CL - norovirus <br />
-	**[[2iph]], [[5wej]] – 3CL + peptide inhibitor <br />
-	**[[2lnc]] – 3CL - NMR<br />
-	**[[5dg6]], [[5dgj]], [[5e0g]], [[5e0h]], [[5e0j]], [[5t6d]], [[5t6f]], [[5t6g]], [[5t61]], [[5t62]], [[4imq]], [[4imz]], [[4in1]], [[4in2]], [[4inh]], [[3ur9]], [[4xbb]], [[4xbc]], [[4xbd]] – 3CL + inhibitor <br />
-
-	**[[1wqs]] – 3C-like residues 1-173 + Hg<br />
-
-	*Mouse norovirus NS6 protease residues 995-1177
-
-	**[[4ash]], [[4x2w]], [[4x2x]], [[4x2y]] - mNS6 (mutant)<br />
-	**[[4x2v]] - mNS6 <br />
-	}}
	==References==		==References==
	{{reflist}}		{{reflist}}
	[[Category:Topic Page]]		[[Category:Topic Page]]

Michal Harel at 18:18, 17 September 2018

Michal Harel — Mon, 17 Sep 2018 18:18:49 GMT

←Older revision		Revision as of 18:18, 17 September 2018
Line 1:		Line 1:
	<StructureSection load='2vj1' size='350' side='right' caption='Human SARS coronavirus proteinase dimer complex with benzoic acid, dimethylamino benzoic acid and DMSO, [[2vj1]]' scene=''>		<StructureSection load='2vj1' size='350' side='right' caption='Human SARS coronavirus proteinase dimer complex with benzoic acid, dimethylamino benzoic acid and DMSO, [[2vj1]]' scene=''>
	==Introduction==		==Introduction==
-	Before the emergence of the SARS-CoV, no research efforts were being directed toward the discovery of antiviral drugs against coronaviruses. The high infectivity and mortality rate established SARS as a significant global threat for which no efficacious therapy was available. Since the epidemic, which began in 2003, new insights into the genomics and pathogenisis of the SARS-CoV revealed several novel potential anti-coronavirus targets. Several proteins encoded by the SARS-CoV could be considered as targets for therapeutic intervention. The focus of this article is the '''SARS-CoV main protease'''.	+	Before the emergence of the SARS-CoV, no research efforts were being directed toward the discovery of antiviral drugs against coronaviruses. The high infectivity and mortality rate established SARS as a significant global threat for which no efficacious therapy was available. Since the epidemic, which began in 2003, new insights into the genomics and pathogenisis of the SARS-CoV revealed several novel potential anti-coronavirus targets. Several proteins encoded by the SARS-CoV could be considered as targets for therapeutic intervention. The focus of this article is the '''SARS-CoV main protease'''. Norovirus protease is an essential enzyme for proteoplytic maturation of norovirus nonstructural proteins and is implicated as a potential antiviral drug target<ref>PMID:23319456</ref>.

	==Coronaviruses==		==Coronaviruses==

Michal Harel at 18:11, 17 September 2018

Michal Harel — Mon, 17 Sep 2018 18:11:38 GMT

←Older revision		Revision as of 18:11, 17 September 2018
Line 62:		Line 62:

	**[[2fyq]], [[3ur6]], [[2fyr]] – 3CL - norovirus <br />		**[[2fyq]], [[3ur6]], [[2fyr]] – 3CL - norovirus <br />
-	**[[2iph]] – 3CL + peptide inhibitor <br />	+	**[[2iph]], [[5wej]] – 3CL + peptide inhibitor <br />
	**[[2lnc]] – 3CL - NMR<br />		**[[2lnc]] – 3CL - NMR<br />
	**[[5dg6]], [[5dgj]], [[5e0g]], [[5e0h]], [[5e0j]], [[5t6d]], [[5t6f]], [[5t6g]], [[5t61]], [[5t62]], [[4imq]], [[4imz]], [[4in1]], [[4in2]], [[4inh]], [[3ur9]], [[4xbb]], [[4xbc]], [[4xbd]] – 3CL + inhibitor <br />		**[[5dg6]], [[5dgj]], [[5e0g]], [[5e0h]], [[5e0j]], [[5t6d]], [[5t6f]], [[5t6g]], [[5t61]], [[5t62]], [[4imq]], [[4imz]], [[4in1]], [[4in2]], [[4inh]], [[3ur9]], [[4xbb]], [[4xbc]], [[4xbd]] – 3CL + inhibitor <br />

Michal Harel at 18:00, 3 October 2017

Michal Harel — Tue, 03 Oct 2017 18:00:11 GMT

←Older revision		Revision as of 18:00, 3 October 2017
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	{{#tree:id=OrganizedByTopic\|openlevels=0\|		{{#tree:id=OrganizedByTopic\|openlevels=0\|

-	*Coronavirus ~~protease~~	+	*Coronavirus 3C-like proteinase residues 3248-3553

-	**[[1q2w]], [[3iwm]], [[3ebn]], [[3d23]], [[5b6o]], [[2gt7]], [[1z1i]], [[2a5a]], [[2c3s]], [[2bx3]], [[2bx4]], [[1uj1]], [[1uk2]], [[1uk3]], [[2duc]], [[2yna]] – 3CLP - SARS coronavirus<br />	+	**[[1q2w]], [[3iwm]], [[3ebn]], [[3d23]], [[5b6o]], [[2gt7]], [[1z1i]], [[2a5a]], [[2c3s]], [[2bx3]], [[2bx4]], [[1uj1]], [[1uk2]], [[1uk3]], [[2duc]], [[2yna]], [[5c3n]] – 3CLP - SARS coronavirus<br />
-	**[[2liz]] – 3CLP ~~C terminal~~ – NMR<br />	+	**[[2liz]] – 3CLP – NMR<br />
-	**[[~~5hih~~]] ~~– 3CLP residues 1109-1275 <br />~~	+	**[[4ylu]], [[4wy3]], [[5c5n]], [[5c5o]], [[4tww]], [[4twy]], [[4zro]], [[2amd]], [[2amq]], [[2amp]], [[1wof]], [[2ynb]], [[3d62]], [[2d2d]] – 3CLP + inhibitor <br />
-	**[[~~4rez~~]], [[~~4rna~~]] ~~– 3CLP residues 1481-1811 <br />~~	+	**[[3atw]], [[3avz]] – 3CLP (mutant) + inhibitor <br />
-	**[[~~5c3n~~]] ~~– 3CLP residues 3248-3553 <br />~~	+
-	**[[2amd]], [[2amq]], [[2amp]], [[1wof]], [[2ynb]], [[~~3atw~~]], [[~~3avz~~]] – 3CLP + inhibitor <br />	+
-	**[[~~4r3d~~]] ~~– 3CLP residues 1481-1811 + inhibitor <br />~~	+
-	**[[~~5gwy~~]] – 3CLP ~~residues 2940-3242~~ + inhibitor <br />	+
	**[[2vj1]], [[3tit]], [[3tiu]] – 3CLP + unsaturated ester<br />		**[[2vj1]], [[3tit]], [[3tiu]] – 3CLP + unsaturated ester<br />
-	**[[3m3s]], [[3m3t]], [[3m3v]], [[3fzd]], [[3f9e]], [[3f9f]], [[3f9g]], [[3f9h]], [[3ea7]], [[3ea8]], [[3ea9]], [[3eaj]], [[3e91]], [[3ee7]], [[2qc2]], [[2qcy]], [[2pwx]], [[2gt8]], [[1z1j]], [[3aw1]] – 3CLP (mutant) <br />	+	**[[3m3s]], [[3m3t]], [[3m3v]], [[3fzd]], [[3f9e]], [[3f9f]], [[3f9g]], [[3f9h]], [[3ea7]], [[3ea8]], [[3ea9]], [[3eaj]], [[3e91]], [[3ee7]], [[2qc2]], [[2qcy]], [[2pwx]], [[2gt8]], [[1z1j]], [[3aw1]], [[4wmd]], [[4wme]], [[4wmf]], [[5b6o]] – 3CLP (mutant) <br />
	**[[2zu2]], [[2zu4]], [[2zu5]], [[3tns]], [[3tnt]], [[3aw0]] – 3CLP + peptidomimetic compound<br />		**[[2zu2]], [[2zu4]], [[2zu5]], [[3tns]], [[3tnt]], [[3aw0]] – 3CLP + peptidomimetic compound<br />
-	**[[3d62]] – 3CLP + halometyl ketone inhibitor <br />
	**[[2z9g]] – 3CLP + benzene + Hg<br />		**[[2z9g]] – 3CLP + benzene + Hg<br />
	**[[2z9j]], [[2z9k]], [[2z9l]] – 3CLP + Zn compound<br />		**[[2z9j]], [[2z9k]], [[2z9l]] – 3CLP + Zn compound<br />
-	**[[2ops]] – 3CLP + phenylalanine derivative inhibitor <br />
	**[[2z3c]], [[2z3d]], [[2z3e]], [[2gx4]], [[1uk4]] – 3CLP + peptide inhibitor <br />		**[[2z3c]], [[2z3d]], [[2z3e]], [[2gx4]], [[1uk4]] – 3CLP + peptide inhibitor <br />
	**[[2gtb]] - 3CLP (mutant) + aza-peptide epoxide inhibitor <br />		**[[2gtb]] - 3CLP (mutant) + aza-peptide epoxide inhibitor <br />
	**[[2a5i]], [[2a5k]] - 3CLP + aza-peptide epoxide inhibitor <br />		**[[2a5i]], [[2a5k]] - 3CLP + aza-peptide epoxide inhibitor <br />
-	**[[2d2d]] – 3CLP + I2

-	*Norovirus protease	+	*Coronavirus papain-like proteinase residues 1481-1811
		+
		+	**[[4rez]], [[4rna]], [[5ko3]] – 3CLP <br />
		+	**[[4r3d]], [[4rsp]] – 3CLP + inhibitor <br />
		+	**[[4rf0]], [[4rf1]] – 3CLP + ubiquitin/RPL40 <br />
		+	**[[5v69]], [[5v6a]] – 3CLP + ubiquitin <br />
		+	**[[5tl6]], [[5tl7]] – 3CLP + ubiquitin-like protein C-terminal <br />
		+	**[[4wur]] – 3CLP (mutant) + ubiquitin <br />
		+
		+	*Coronavirus other regions
		+
		+	**[[5gwy]] – 3CLP residues 2940-3242 + inhibitor <br />
		+	**[[5hih]] – 3CLP residues 1109-1275 <br />
		+
		+	*Norovirus 3C-like (or Norwalk) protease residues 1101-1281
		+
		+	**[[2fyq]], [[3ur6]], [[2fyr]] – 3CL - norovirus <br />
		+	**[[2iph]] – 3CL + peptide inhibitor <br />
		+	**[[2lnc]] – 3CL - NMR<br />
		+	**[[5dg6]], [[5dgj]], [[5e0g]], [[5e0h]], [[5e0j]], [[5t6d]], [[5t6f]], [[5t6g]], [[5t61]], [[5t62]], [[4imq]], [[4imz]], [[4in1]], [[4in2]], [[4inh]], [[3ur9]], [[4xbb]], [[4xbc]], [[4xbd]] – 3CL + inhibitor <br />
		+
		+	**[[1wqs]] – 3C-like residues 1-173 + Hg<br />
		+
		+	*Mouse norovirus NS6 protease residues 995-1177

-	**[[~~2iph~~]] ~~– 3C-pro + peptide~~ - ~~norovirus~~ <br />	+	**[[4ash]], [[4x2w]], [[4x2x]], [[4x2y]] - mNS6 (mutant)<br />
-	**[[~~1wqs~~]] ~~– 3C~~-~~pro + Hg~~	+	**[[4x2v]] - mNS6 <br />
	}}		}}
	==References==		==References==
	{{reflist}}		{{reflist}}
	[[Category:Topic Page]]		[[Category:Topic Page]]

Michal Harel at 22:02, 2 October 2017

Michal Harel — Mon, 02 Oct 2017 22:02:07 GMT

←Older revision		Revision as of 22:02, 2 October 2017
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-
	<StructureSection load='2vj1' size='350' side='right' caption='Human SARS coronavirus proteinase dimer complex with benzoic acid, dimethylamino benzoic acid and DMSO, [[2vj1]]' scene=''>		<StructureSection load='2vj1' size='350' side='right' caption='Human SARS coronavirus proteinase dimer complex with benzoic acid, dimethylamino benzoic acid and DMSO, [[2vj1]]' scene=''>
	==Introduction==		==Introduction==
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	**[[1q2w]], [[3iwm]], [[3ebn]], [[3d23]], [[5b6o]], [[2gt7]], [[1z1i]], [[2a5a]], [[2c3s]], [[2bx3]], [[2bx4]], [[1uj1]], [[1uk2]], [[1uk3]], [[2duc]], [[2yna]] – 3CLP - SARS coronavirus<br />		**[[1q2w]], [[3iwm]], [[3ebn]], [[3d23]], [[5b6o]], [[2gt7]], [[1z1i]], [[2a5a]], [[2c3s]], [[2bx3]], [[2bx4]], [[1uj1]], [[1uk2]], [[1uk3]], [[2duc]], [[2yna]] – 3CLP - SARS coronavirus<br />
	**[[2liz]] – 3CLP C terminal – NMR<br />		**[[2liz]] – 3CLP C terminal – NMR<br />
		+	**[[5hih]] – 3CLP residues 1109-1275 <br />
		+	**[[4rez]], [[4rna]] – 3CLP residues 1481-1811 <br />
		+	**[[5c3n]] – 3CLP residues 3248-3553 <br />
	**[[2amd]], [[2amq]], [[2amp]], [[1wof]], [[2ynb]], [[3atw]], [[3avz]] – 3CLP + inhibitor <br />		**[[2amd]], [[2amq]], [[2amp]], [[1wof]], [[2ynb]], [[3atw]], [[3avz]] – 3CLP + inhibitor <br />
		+	**[[4r3d]] – 3CLP residues 1481-1811 + inhibitor <br />
		+	**[[5gwy]] – 3CLP residues 2940-3242 + inhibitor <br />
	**[[2vj1]], [[3tit]], [[3tiu]] – 3CLP + unsaturated ester<br />		**[[2vj1]], [[3tit]], [[3tiu]] – 3CLP + unsaturated ester<br />
	**[[3m3s]], [[3m3t]], [[3m3v]], [[3fzd]], [[3f9e]], [[3f9f]], [[3f9g]], [[3f9h]], [[3ea7]], [[3ea8]], [[3ea9]], [[3eaj]], [[3e91]], [[3ee7]], [[2qc2]], [[2qcy]], [[2pwx]], [[2gt8]], [[1z1j]], [[3aw1]] – 3CLP (mutant) <br />		**[[3m3s]], [[3m3t]], [[3m3v]], [[3fzd]], [[3f9e]], [[3f9f]], [[3f9g]], [[3f9h]], [[3ea7]], [[3ea8]], [[3ea9]], [[3eaj]], [[3e91]], [[3ee7]], [[2qc2]], [[2qcy]], [[2pwx]], [[2gt8]], [[1z1j]], [[3aw1]] – 3CLP (mutant) <br />

Michal Harel at 11:08, 24 November 2016

Michal Harel — Thu, 24 Nov 2016 11:08:10 GMT

←Older revision		Revision as of 11:08, 24 November 2016
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-	~~{{STRUCTURE_2vj1\| PDB=2vj1 \| SIZE=400\| SCENE= \|right\|CAPTION=Human SARS coronavirus proteinase dimer complex with benzoic acid, dimethylamino benzoic acid and DMSO, [[2vj1]] }}~~	+
	<StructureSection load='2vj1' size='350' side='right' caption='Human SARS coronavirus proteinase dimer complex with benzoic acid, dimethylamino benzoic acid and DMSO, [[2vj1]]' scene=''>		<StructureSection load='2vj1' size='350' side='right' caption='Human SARS coronavirus proteinase dimer complex with benzoic acid, dimethylamino benzoic acid and DMSO, [[2vj1]]' scene=''>
	==Introduction==		==Introduction==