PDBsum entry 4xbc

Hydrolase/hydrolase inhibitor

PDB id: 4xbc

Contents

Protein chain

174 a.a.

Ligands

M40

PG4

Waters ×160

PDB id:

4xbc

Name:

Hydrolase/hydrolase inhibitor

Title:

1.60 a resolution structure of norovirus 3cl protease complex with a covalently bound dipeptidyl inhibitor (1r,2s)-2-({n-[(benzyloxy) carbonyl]-3-cyclohexyl-l-alanyl}amino)-1-hydroxy-3-[(3s)-2- oxopyrrolidin-3-yl]propane-1-sulfonic acid (hexagonal form)

Structure:

3c-like protease. Chain: a. Engineered: yes

Source:

Norwalk virus (strain gi/human/united states/norwalk/1968). Hu/nv/nv/1968/us. Organism_taxid: 524364. Strain: gi/human/united states/norwalk/1968. Gene: orf1. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

1.60Å R-factor: 0.164 R-free: 0.175

Authors:

S.Lovell,K.P.Battaile,N.Mehzabeen,A.C.G.Kankanamalage,Y.Kim, P.M.Weerawarna,R.A.Z.Uy,V.C.Damalanka,S.R.Mandadapu,K.R.Alliston, W.C.Groutas,K.-O.Chang

Key ref:

A.C.Galasiti Kankanamalage et al. (2015). Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies. J Med Chem, 58, 3144-3155. PubMed id: 25761614 DOI: 10.1021/jm5019934

Date:

16-Dec-14 Release date: 25-Mar-15

Protein chain

Q83883  (POLG_NVN68) -  Genome polyprotein from Norovirus (strain Human/NoV/United States/Norwalk/1968/GI)

Seq: 1789 a.a.

Struc: 174 a.a.*

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

Enzyme reactions

• Enzyme class 1: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
• Enzyme class 2: E.C.3.4.22.66 - calicivirin.
• Enzyme class 3: E.C.3.6.1.15 - nucleoside-triphosphate phosphatase.
• Reaction: a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + phosphate + H⁺

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/jm5019934

J Med Chem 58:3144-3155 (2015)

PubMed id: 25761614

Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies.

A.C.Galasiti Kankanamalage, Y.Kim, P.M.Weerawarna, R.A.Uy, V.C.Damalanka, S.R.Mandadapu, K.R.Alliston, N.Mehzabeen, K.P.Battaile, S.Lovell, K.O.Chang, W.C.Groutas.

ABSTRACT

Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.