PDBsum entry 1cqq

Hydrolase

PDB id: 1cqq

Contents

Protein chain

180 a.a. *

Ligands

AG7

Waters ×663

* Residue conservation analysis

PDB id:

1cqq

Name:

Hydrolase

Title:

Type 2 rhinovirus 3c protease with ag7088 inhibitor

Structure:

Type 2 rhinovirus 3c protease. Chain: a

Source:

Human rhinovirus 2. Organism_taxid: 12130

Resolution:

1.85Å R-factor: not given

Authors:

D.Matthews,R.A.Ferre

Key ref:

D.A.Matthews et al. (1999). Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes. Proc Natl Acad Sci U S A, 96, 11000-11007. PubMed id: 10500114 DOI: 10.1073/pnas.96.20.11000

Date:

10-Aug-99 Release date: 20-Sep-99

Protein chain

P04936  (POLG_HRV2) -  Genome polyprotein from Human rhinovirus 2

Seq: 2150 a.a.

Struc: 180 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
• Enzyme class 3: E.C.3.4.22.28 - picornain 3C.
• Reaction: Selective cleavage of Gln-|-Gly bond in the poliovirus polyprotein. In other picornavirus reactions Glu may be substituted for Gln, and Ser or Thr for Gly.
• Enzyme class 4: E.C.3.4.22.29 - picornain 2A.
• Reaction: Selective cleavage of Tyr-|-Gly bond in the picornavirus polyprotein. In other picornavirus reactions Glu may be substituted for Gln, and Ser or Thr for Gly.
• Enzyme class 5: 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: 10.1073/pnas.96.20.11000

Proc Natl Acad Sci U S A 96:11000-11007 (1999)

PubMed id: 10500114

Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes.

D.A.Matthews, P.S.Dragovich, S.E.Webber, S.A.Fuhrman, A.K.Patick, L.S.Zalman, T.F.Hendrickson, R.A.Love, T.J.Prins, J.T.Marakovits, R.Zhou, J.Tikhe, C.E.Ford, J.W.Meador, R.A.Ferre, E.L.Brown, S.L.Binford, M.A.Brothers, D.M.DeLisle, S.T.Worland.

ABSTRACT

Human rhinoviruses, the most important etiologic agents of the common cold, are messenger-active single-stranded monocistronic RNA viruses that have evolved a highly complex cascade of proteolytic processing events to control viral gene expression and replication. Most maturation cleavages within the precursor polyprotein are mediated by rhinovirus 3C protease (or its immediate precursor, 3CD), a cysteine protease with a trypsin-like polypeptide fold. High-resolution crystal structures of the enzyme from three viral serotypes have been used for the design and elaboration of 3C protease inhibitors representing different structural and chemical classes. Inhibitors having alpha,beta-unsaturated carbonyl groups combined with peptidyl-binding elements specific for 3C protease undergo a Michael reaction mediated by nucleophilic addition of the enzyme's catalytic Cys-147, resulting in covalent-bond formation and irreversible inactivation of the viral protease. Direct inhibition of 3C proteolytic activity in virally infected cells treated with these compounds can be inferred from dose-dependent accumulations of viral precursor polyproteins as determined by SDS/PAGE analysis of radiolabeled proteins. Cocrystal-structure-assisted optimization of 3C-protease-directed Michael acceptors has yielded molecules having extremely rapid in vitro inactivation of the viral protease, potent antiviral activity against multiple rhinovirus serotypes and low cellular toxicity. Recently, one compound in this series, AG7088, has entered clinical trials.

Selected figure(s)

Figure 1.
Fig. 1. Rhinovirus 3C protease inhibitors. K[i], inhibition constant; k[obs], observed rate of inactivation; I, inhibitor concentration.

Figure 3.
Fig. 3. Compound III bound to serotype 2 human rhinovirus 3C protease. Color coding is the same as in Fig. 2.

Figures were selected by an automated process.