PDBsum entry 4ow0

Hydrolase/hydrolase inhibitor

PDB id: 4ow0

Contents

Protein chains

312 a.a.

260 a.a.

Ligands

S88 ×2

DMS ×3

GOL

Metals

_ZN ×2

Waters ×184

PDB id:

4ow0

Name:

Hydrolase/hydrolase inhibitor

Title:

X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases

Structure:

Papain-like protease. Chain: a, b. Synonym: non-structural protein 3, nsp3, pl2-pro, pl-pro, sars coronavirus main proteinase. Engineered: yes

Source:

Sars coronavirus. Organism_taxid: 228330. Strain: urbani. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.10Å R-factor: 0.178 R-free: 0.205

Authors:

Y.M.Baez-Santos,A.Mesecar

Key ref:

Y.M.Báez-Santos et al. (2014). X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases. J Med Chem, 57, 2393-2412. PubMed id: 24568342 DOI: 10.1021/jm401712t

Date:

28-Jan-14 Release date: 23-Apr-14

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: 260 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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

DOI no: 10.1021/jm401712t

J Med Chem 57:2393-2412 (2014)

PubMed id: 24568342

X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases.

Y.M.Báez-Santos, S.J.Barraza, M.W.Wilson, M.P.Agius, A.M.Mielech, N.M.Davis, S.C.Baker, S.D.Larsen, A.D.Mesecar.

ABSTRACT

Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected Vero E6 cells and broadened specificity toward the homologous PLP2 enzyme from the human coronavirus NL63. Selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquitinating enzymes (DUBs), and no significant cytotoxicity in Vero E6 and HEK293 cell lines is observed. X-ray structural analyses of inhibitor-bound crystal structures revealed subtle differences between binding modes of the initial benzodioxolane lead (15g) and the most potent analogues 3k and 3j, featuring a monofluoro substitution at para and meta positions of the benzyl ring, respectively. Finally, the less lipophilic bis(amide) 3e and methoxypyridine 5c exhibit significantly improved metabolic stability and are viable candidates for advancing to in vivo studies.