PDBsum entry 3mj5

Viral protein

PDB id: 3mj5

Contents

Protein chains

312 a.a. *

262 a.a. *

Ligands

GRM ×2

Metals

_ZN ×2

Waters ×119

* Residue conservation analysis

PDB id:

3mj5

Name:

Viral protein

Title:

Severe acute respiratory syndrome-coronavirus papain-like protease inhibitors: design, synthesis, protein-ligand x-ray structure and biological evaluation

Structure:

Replicase polyprotein 1a. Chain: a, b. Fragment: sars polyprotein residues 1544-1855. Synonym: pp1a, orf1a polyprotein, non-structural protein 1, nsp1, leader protein, non-structural protein 2, nsp2, p65 homolog, non- structural protein 3, nsp3, papain-like proteinase, pl-pro, pl2-pro, non-structural protein 4, nsp4, 3c-like proteinase, 3cl-pro, 3clp, nsp5, non-structural protein 6, nsp6, non-structural protein 7, nsp7, non-structural protein 8, nsp8, non-structural protein 9, nsp9, non-

Source:

Sars coronavirus. Sars-cov. Organism_taxid: 227859. Strain: urbani. Gene: 1a, orf1 (nsp3) residues 1544-1855. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.63Å R-factor: 0.211 R-free: 0.248

Authors:

A.D.Mesecar,K.M.Ratia,S.D.Pegan

Key ref:

A.K.Ghosh et al. (2010). Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation. J Med Chem, 53, 4968-4979. PubMed id: 20527968

Date:

12-Apr-10 Release date: 30-Jun-10

Protein chain

P0C6U8  (R1A_CVHSA) -  Replicase polyprotein 1a from Severe acute respiratory syndrome coronavirus

Seq: 4382 a.a.

Struc: 312 a.a.

Protein chain

P0C6U8  (R1A_CVHSA) -  Replicase polyprotein 1a from Severe acute respiratory syndrome coronavirus

Seq: 4382 a.a.

Struc: 262 a.a.

Enzyme reactions

• Enzyme class 1: Chains A, B: 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 2: Chains A, B: 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 3: Chains A, B: E.C.3.4.22.- - ?????
• Enzyme class 4: Chains A, B: E.C.3.4.22.69 - Sars coronavirus main proteinase.

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

Added reference

J Med Chem 53:4968-4979 (2010)

PubMed id: 20527968

Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation.

A.K.Ghosh, J.Takayama, K.V.Rao, K.Ratia, R.Chaudhuri, D.C.Mulhearn, H.Lee, D.B.Nichols, S.Baliji, S.C.Baker, M.E.Johnson, A.D.Mesecar.

ABSTRACT

The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15 h (enzyme IC(50) = 0.56 microM; antiviral EC(50) = 9.1 microM) and the corresponding (R)-Me 15 g (IC(50) = 0.32 microM; antiviral EC(50) = 9.1 microM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15 g-bound SARS-CoV PLpro and a corresponding model of 15 h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.