PDBsum entry 2gx4

Hydrolase

PDB id: 2gx4

Contents

Protein chain

306 a.a. *

Ligands

NOL

Waters ×257

* Residue conservation analysis

PDB id:

2gx4

Name:

Hydrolase

Title:

Crystal structure of sars coronavirus 3cl protease inhibitor complex

Structure:

3c-like proteinase. Chain: a. Fragment: residues 1-306. Synonym: 3cl protease, 3cl-pro, 3clp, replicase polyprotein 1ab. Engineered: yes

Source:

Sars coronavirus. Organism_taxid: 227859. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.93Å R-factor: 0.205 R-free: 0.249

Authors:

M.F.Hsu,A.H.-J.Wang

Key ref:

S.Yang et al. (2006). Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor. J Med Chem, 49, 4971-4980. PubMed id: 16884309 DOI: 10.1021/jm0603926

Date:

08-May-06 Release date: 08-May-07

Protein chain

P0C6X7  (R1AB_CVHSA) -  Replicase polyprotein 1ab from Severe acute respiratory syndrome coronavirus

Seq: 7073 a.a.

Struc: 306 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.1.1.- - ?????
• Enzyme class 3: E.C.2.1.1.56 - mRNA (guanine-N(7))-methyltransferase.
• 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
• Enzyme class 4: E.C.2.1.1.57 - methyltransferase cap1.
• 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⁺
• Enzyme class 5: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
• Enzyme class 6: E.C.2.7.7.50 - mRNA guanylyltransferase.
• Reaction: a 5'-end diphospho-ribonucleoside in mRNA + GTP + H⁺ = a 5'-end (5'-triphosphoguanosine)-ribonucleoside in mRNA + diphosphate
• Enzyme class 7: E.C.3.1.13.- - ?????
• Enzyme class 8: E.C.3.4.19.12 - ubiquitinyl hydrolase 1.
• 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.- - ?????
• Enzyme class 10: E.C.3.4.22.69 - Sars coronavirus main proteinase.
• Enzyme class 11: E.C.3.6.4.12 - Dna helicase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺
• Enzyme class 12: E.C.3.6.4.13 - Rna helicase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺
• Enzyme class 13: E.C.4.6.1.- - ?????

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: 10.1021/jm0603926

J Med Chem 49:4971-4980 (2006)

PubMed id: 16884309

Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor.

S.Yang, S.J.Chen, M.F.Hsu, J.D.Wu, C.T.Tseng, Y.F.Liu, H.C.Chen, C.W.Kuo, C.S.Wu, L.W.Chang, W.C.Chen, S.Y.Liao, T.Y.Chang, H.H.Hung, H.L.Shr, C.Y.Liu, Y.A.Huang, L.Y.Chang, J.C.Hsu, C.J.Peters, A.H.Wang, M.C.Hsu.

ABSTRACT

A potent SARS coronavirus (CoV) 3CL protease inhibitor (TG-0205221, Ki = 53 nM) has been developed. TG-0205221 showed remarkable activity against SARS CoV and human coronavirus (HCoV) 229E replications by reducing the viral titer by 4.7 log (at 5 microM) for SARS CoV and 5.2 log (at 1.25 microM) for HCoV 229E. The crystal structure of TG-0205221 (resolution = 1.93 A) has revealed a unique binding mode comprising a covalent bond, hydrogen bonds, and numerous hydrophobic interactions. Structural comparisons between TG-0205221 and a natural peptide substrate were also discussed. This information may be applied toward the design of other 3CL protease inhibitors.