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PDBsum entry 2a5i
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Hydrolase PDB id
2a5i

 

 

 

 

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JSmol PyMol  
Contents
Protein chain
306 a.a. *
Ligands
AZP
EDO
GOL
Waters ×256
* Residue conservation analysis
PDB id:
2a5i
Name: Hydrolase
Title: Crystal structures of sars coronavirus main peptidase inhibited by an aza-peptide epoxide in the space group c2
Structure: 3c-like peptidase. Chain: a. Synonym: 3cl-pro, 3clp, nsp2. Engineered: yes
Source: Sars coronavirus. Organism_taxid: 227859. Strain: sars. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.88Å     R-factor:   0.200     R-free:   0.242
Authors: T.-W.Lee,M.M.Cherney,C.Huitema,J.Liu,K.E.James,J.C.Powers,L.D.Eltis, M.N.James
Key ref:
T.W.Lee et al. (2005). Crystal structures of the main peptidase from the SARS coronavirus inhibited by a substrate-like aza-peptide epoxide. J Mol Biol, 353, 1137-1151. PubMed id: 16219322 DOI: 10.1016/j.jmb.2005.09.004
Date:
30-Jun-05     Release date:   25-Oct-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P0C6X7  (R1AB_CVHSA) -  Replicase polyprotein 1ab from Severe acute respiratory syndrome coronavirus
Seq:
Struc: 		 
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Seq:
Struc: 		7073 a.a.
306 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.2.1.1.-  - ?????
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 3: E.C.2.1.1.56  - mRNA (guanine-N(7))-methyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: a 5'-end (5'-triphosphoguanosine)-ribonucleoside in mRNA + S-adenosyl-L- methionine = a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-ribonucleoside in mRNA + S-adenosyl-L-homocysteine
5'-end (5'-triphosphoguanosine)-ribonucleoside in mRNA
 + S-adenosyl-L- methionine
 = 5'-end (N(7)-methyl 5'-triphosphoguanosine)-ribonucleoside in mRNA
 + S-adenosyl-L-homocysteine
   Enzyme class 4: E.C.2.1.1.57  - methyltransferase cap1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-ribonucleoside in mRNA + S-adenosyl-L-methionine = a 5'-end (N(7)-methyl 5'-triphosphoguanosine)- (2'-O-methyl-ribonucleoside) in mRNA + S-adenosyl-L-homocysteine + H+
5'-end (N(7)-methyl 5'-triphosphoguanosine)-ribonucleoside in mRNA
 + S-adenosyl-L-methionine
 = 5'-end (N(7)-methyl 5'-triphosphoguanosine)- (2'-O-methyl-ribonucleoside) in mRNA
 + S-adenosyl-L-homocysteine
 + H(+)
   Enzyme class 5: E.C.2.7.7.48  - RNA-directed Rna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
RNA(n)
 + ribonucleoside 5'-triphosphate
 = RNA(n+1)
 + diphosphate
   Enzyme class 6: E.C.2.7.7.50  - mRNA guanylyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: a 5'-end diphospho-ribonucleoside in mRNA + GTP + H+ = a 5'-end (5'-triphosphoguanosine)-ribonucleoside in mRNA + diphosphate
5'-end diphospho-ribonucleoside in mRNA
 + GTP
 + H(+)
 = 5'-end (5'-triphosphoguanosine)-ribonucleoside in mRNA
 + diphosphate
   Enzyme class 7: E.C.3.1.13.-  - ?????
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 8: E.C.3.4.19.12  - ubiquitinyl hydrolase 1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Thiol-dependent hydrolysis of ester, thiolester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).
   Enzyme class 9: E.C.3.4.22.-  - ?????
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 10: E.C.3.4.22.69  - Sars coronavirus main proteinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 11: E.C.3.6.4.12  - Dna helicase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + H2O = ADP + phosphate + H+
ATP
 + H2O
 = ADP
 + phosphate
 + H(+)
   Enzyme class 12: E.C.3.6.4.13  - Rna helicase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + H2O = ADP + phosphate + H+
ATP
 + H2O
 = ADP
 + phosphate
 + H(+)
   Enzyme class 13: E.C.4.6.1.-  - ?????
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1016/j.jmb.2005.09.004 J Mol Biol 353:1137-1151 (2005)
PubMed id: 16219322  
 
 
Crystal structures of the main peptidase from the SARS coronavirus inhibited by a substrate-like aza-peptide epoxide.
T.W.Lee, M.M.Cherney, C.Huitema, J.Liu, K.E.James, J.C.Powers, L.D.Eltis, M.N.James.
 
  ABSTRACT  
 
The main peptidase (M(pro)) from the coronavirus (CoV) causing severe acute respiratory syndrome (SARS) is one of the most attractive molecular targets for the development of anti-SARS agents. We report the irreversible inhibition of SARS-CoV M(pro) by an aza-peptide epoxide (APE; k(inact)/K(i) = 1900(+/-400) M(-1) s(-1)). The crystal structures of the M(pro):APE complex in the space groups C2 and P2(1)2(1)2(1) revealed the formation of a covalent bond between the catalytic Cys145 S(gamma) atom of the peptidase and the epoxide C3 atom of the inhibitor, substantiating the mode of action of this class of cysteine-peptidase inhibitors. The aza-peptide component of APE binds in the substrate-binding regions of M(pro) in a substrate-like manner, with excellent structural and chemical complementarity. In addition, the crystal structure of unbound M(pro) in the space group C2 revealed that the "N-fingers" (N-terminal residues 1 to 7) of both protomers of M(pro) are well defined and the substrate-binding regions of both protomers are in the catalytically competent conformation at the crystallization pH of 6.5, contrary to the previously determined crystal structures of unbound M(pro) in the space group P2(1).
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Binding of APE (orange) in the substrate-binding regions of SARS-CoV Mpro. (a) Stereo view of the outstanding density in the F[o] -F[c] map for the structures of the Mpro:APE complex and protomer B of the Click to view the MathML source- [0?wchp=dGLbVlz-zSkWA] complex. (b) The corresponding stereo view for protomer A of the Click to view the MathML source- [0?wchp=dGLbVlz-zSkWA] complex. 		Figure 7.
Figure 7. Models for each of the four diastereomers of Cbz-Leu-Phe-AGln-EP-COOEt binding to SARS-CoV Mpro before the nucleophilic attack by the Cys145 Sg atom of the peptidase. (a) 2S, 3S, (b) 2R, 3R, (c) 2S, 3R, (d) 2R, 3S.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 353, 1137-1151) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
17931870 C.Niu, J.Yin, J.Zhang, J.C.Vederas, and M.N.James (2008).
Molecular docking identifies the binding of 3-chloropyridine moieties specifically to the S1 pocket of SARS-CoV Mpro.
  Bioorg Med Chem, 16, 293-302.  
18305031 J.Shi, J.Sivaraman, and J.Song (2008).
Mechanism for controlling the dimer-monomer switch and coupling dimerization to catalysis of the severe acute respiratory syndrome coronavirus 3C-like protease.
  J Virol, 82, 4620-4629.
PDB code: 2qcy
  19203466 M.R.Suresh, P.K.Bhatnagar, and D.Das (2008).
Molecular targets for diagnostics and therapeutics of severe acute respiratory syndrome (SARS-CoV).
  J Pharm Pharm Sci, 11, 1s.  
18305043 N.Zhong, S.Zhang, P.Zou, J.Chen, X.Kang, Z.Li, C.Liang, C.Jin, and B.Xia (2008).
Without its N-finger, the main protease of severe acute respiratory syndrome coronavirus can form a novel dimer through its C-terminal domain.
  J Virol, 82, 4227-4234.  
17397959 R.L.Graham, J.S.Sparks, L.D.Eckerle, A.C.Sims, and M.R.Denison (2008).
SARS coronavirus replicase proteins in pathogenesis.
  Virus Res, 133, 88.  
17977841 S.Chen, T.Hu, J.Zhang, J.Chen, K.Chen, J.Ding, H.Jiang, and X.Shen (2008).
Mutation of Gly-11 on the dimer interface results in the complete crystallographic dimer dissociation of severe acute respiratory syndrome coronavirus 3C-like protease: crystal structure with molecular dynamics simulations.
  J Biol Chem, 283, 554-564.
PDB code: 2pwx
18094151 X.Xue, H.Yu, H.Yang, F.Xue, Z.Wu, W.Shen, J.Li, Z.Zhou, Y.Ding, Q.Zhao, X.C.Zhang, M.Liao, M.Bartlam, and Z.Rao (2008).
Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design.
  J Virol, 82, 2515-2527.
PDB codes: 2q6d 2q6f 2q6g
19649165 A.K.Ghosh, K.Xi, M.E.Johnson, S.C.Baker, and A.D.Mesecar (2007).
Progress in Anti-SARS Coronavirus Chemistry, Biology and Chemotherapy.
  Annu Rep Med Chem, 41, 183-196.  
17218315 D.Cuerrier, T.Moldoveanu, R.L.Campbell, J.Kelly, B.Yoruk, S.H.Verhelst, D.Greenbaum, M.Bogyo, and P.L.Davies (2007).
Development of calpain-specific inactivators by screening of positional scanning epoxide libraries.
  J Biol Chem, 282, 9600-9611.
PDB codes: 2nqg 2nqi
17142288 H.P.Chang, C.Y.Chou, and G.G.Chang (2007).
Reversible unfolding of the severe acute respiratory syndrome coronavirus main protease in guanidinium chloride.
  Biophys J, 92, 1374-1383.  
17722121 Y.M.Shao, W.B.Yang, H.P.Peng, M.F.Hsu, K.C.Tsai, T.H.Kuo, A.H.Wang, P.H.Liang, C.H.Lin, A.S.Yang, and C.H.Wong (2007).
Structure-based design and synthesis of highly potent SARS-CoV 3CL protease inhibitors.
  Chembiochem, 8, 1654-1657.  
16597209 E.De Clercq (2006).
Potential antivirals and antiviral strategies against SARS coronavirus infections.
  Expert Rev Anti Infect Ther, 4, 291-302.  
16565086 H.Chen, P.Wei, C.Huang, L.Tan, Y.Liu, and L.Lai (2006).
Only one protomer is active in the dimer of SARS 3C-like proteinase.
  J Biol Chem, 281, 13894-13898.  
17154528 J.Barrila, U.Bacha, and E.Freire (2006).
Long-range cooperative interactions modulate dimerization in SARS 3CLpro.
  Biochemistry, 45, 14908-14916.  
17085042 J.R.Mesters, J.Tan, and R.Hilgenfeld (2006).
Viral enzymes.
  Curr Opin Struct Biol, 16, 776-786.  
16895471 M.N.James (2006).
The peptidases from fungi and viruses.
  Biol Chem, 387, 1023-1029.  
16688706 S.I.Al-Gharabli, S.T.Shah, S.Weik, M.F.Schmidt, J.R.Mesters, D.Kuhn, G.Klebe, R.Hilgenfeld, and J.Rademann (2006).
An efficient method for the synthesis of peptide aldehyde libraries employed in the discovery of reversible SARS coronavirus main protease (SARS-CoV Mpro) inhibitors.
  Chembiochem, 7, 1048-1055.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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