PDBsum entry 5y3e

Hydrolase

PDB id: 5y3e

Contents

Protein chain

317 a.a.

Ligands

GOL ×3

Metals

_ZN

_NA ×5

Waters ×214

PDB id:

5y3e

Name:

Hydrolase

Title:

Crystal structure of sars coronavirus papain-like protease in complex with glycerol

Structure:

Replicase polyprotein 1a. Chain: a. Fragment: unp residues 1541-1854. Synonym: pp1a,orf1a polyprotein. Engineered: yes

Source:

Human sars coronavirus. Sars-cov. Organism_taxid: 227859. Gene: 1a. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.65Å R-factor: 0.164 R-free: 0.199

Authors:

M.H.Lin,C.Y.Chou

Key ref:

M.H.Lin et al. (2018). Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes. Antiviral Res, 150, 155-163. PubMed id: 29289665 DOI: 10.1016/j.antiviral.2017.12.015

Date:

28-Jul-17 Release date: 10-Jan-18

Protein chain

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

Seq: 4382 a.a.

Struc: 317 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: 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: 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: E.C.3.4.22.- - ?????
• Enzyme class 4: 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

DOI no: 10.1016/j.antiviral.2017.12.015

Antiviral Res 150:155-163 (2018)

PubMed id: 29289665

Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes.

M.H.Lin, D.C.Moses, C.H.Hsieh, S.C.Cheng, Y.H.Chen, C.Y.Sun, C.Y.Chou.

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in southern China in late 2002 and caused a global outbreak with a fatality rate around 10% in 2003. Ten years later, a second highly pathogenic human CoV, MERS-CoV, emerged in the Middle East and has spread to other countries in Europe, North Africa, North America and Asia. As of November 2017, MERS-CoV had infected at least 2102 people with a fatality rate of about 35% globally, and hence there is an urgent need to identify antiviral drugs that are active against MERS-CoV. Here we show that a clinically available alcohol-aversive drug, disulfiram, can inhibit the papain-like proteases (PL^pros) of MERS-CoV and SARS-CoV. Our findings suggest that disulfiram acts as an allosteric inhibitor of MERS-CoV PL^probut as a competitive (or mixed) inhibitor of SARS-CoV PL^pro. The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PL^proby disulfiram, while synergistic inhibition of MERS-CoV PL^proby disulfiram and 6-thioguanine or mycophenolic acid implies the potential for combination treatments using these three clinically available drugs.