PDBsum entry 1vrh

Virus

PDB id: 1vrh

Contents

Protein chains

273 a.a. *

255 a.a. *

236 a.a. *

40 a.a. *

Ligands

SD8

* Residue conservation analysis

PDB id:

1vrh

Name:

Virus

Title:

Hrv14/sdz 880-061 complex

Structure:

Rhinovirus 14. Chain: 1. Synonym: hrv14. Engineered: yes. Mutation: yes. Rhinovirus 14. Chain: 2. Synonym: hrv14. Engineered: yes.

Source:

Human rhinovirus 14. Organism_taxid: 12131. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_taxid: 9606

Resolution:

3.00Å R-factor: not given

Authors:

D.A.Oren,A.Zhang,E.Arnold

Key ref:

D.A.Oren et al. (1996). Synthesis and activity of piperazine-containing antirhinoviral agents and crystal structure of SDZ 880-061 bound to human rhinovirus 14. J Mol Biol, 259, 120-134. PubMed id: 8648640 DOI: 10.1006/jmbi.1996.0307

Date:

26-Feb-96 Release date: 12-Feb-97

Protein chain

P03303  (POLG_HRV14) -  Genome polyprotein from Human rhinovirus 14

Seq: 2179 a.a.

Struc: 273 a.a.

Protein chain

P03303  (POLG_HRV14) -  Genome polyprotein from Human rhinovirus 14

Seq: 2179 a.a.

Struc: 255 a.a.*

Protein chain

P03303  (POLG_HRV14) -  Genome polyprotein from Human rhinovirus 14

Seq: 2179 a.a.

Struc: 236 a.a.

Protein chain

P03303  (POLG_HRV14) -  Genome polyprotein from Human rhinovirus 14

Seq: 2179 a.a.

Struc: 40 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: Chains 1, 2, 3, 4: E.C.2.7.7.48 - RNA-directed Rna polymerase.
• Reaction: RNA(n) + a ribonucleoside 5'-triphosphate = RNA(n+1) + diphosphate
• Enzyme class 3: Chains 1, 2, 3, 4: 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: Chains 1, 2, 3, 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: Chains 1, 2, 3, 4: 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: 10.1006/jmbi.1996.0307

J Mol Biol 259:120-134 (1996)

PubMed id: 8648640

Synthesis and activity of piperazine-containing antirhinoviral agents and crystal structure of SDZ 880-061 bound to human rhinovirus 14.

D.A.Oren, A.Zhang, H.Nesvadba, B.Rosenwirth, E.Arnold.

ABSTRACT

A series of antipicornaviral agents containing piperazinyl moieties was synthesized with the objective of obtaining a compound with a broad spectrum of antirhinovirus activity, high potency (< or = 0.003 microgram/ml), and low cytotoxicity (> or = 30 micrograms/ml). Five compounds of this series were evaluated in detail for efficacy against various HRV serotypes. The agent SDZ 880-061, containing the benzothiazine moiety SDZ 108-075, which is particularly active against HRV14, and the thiazolyl acetic acid ester group of SDZ 89-124, which is potent against HRV1B, indeed has a relatively broad antiviral spectrum. SDZ 880-061 inhibited 85% of 89 HRV serotypes tested at a concentration of < or = 3 micrograms/ml. The 3.0 A resolution X-ray structure of SDZ 880-061 bound to HRV14 has revealed the binding characteristics of this potent compound. It binds in the same pocket as other capsid-binding antiviral agents characterized to date, leaving the innermost portion of the pocket vacant. The binding causes similar, although less extensive, alterations of the HRV14 VP1 backbone conformation (residues 100 to 110, 151 to 159, and 213 to 224) compared to other antiviral agents analyzed structurally. Although the contacts between SDZ 880-061 and HRV14 are mostly of hydrophobic character, the inhibitor has three relatively short polar interactions with residues of VP1 that represent potential hydrogen bonds. The amount of solvent-accessible surface area of SDZ 880-061 buried in the complex (613 A2) is within the range of that observed in protein-protein interfaces. The observed influence of time of addition or removal of SDZ 880-061 on virus yield and on the infectious-center formation indicates that the compound primarily interferes with HRV14 cellular attachment. Since it is assumed that uncoating requires virion instability and/or flexibility, the finding that SDZ 880-061 has only a marginal effect on uncoating may be due to the fact that it does not completely fill the hydrophobic pocket.

Selected figure(s)

Figure 2.
Figure 2. Stereoview of the electron density in the region of the antiviral binding pocket. The map is calculated using the native phases and coefficients of kFnative - (1 - k)Fcomplex (k = 0.65) contoured at 2s. SDZ 880-061 is modeled into the density as described in the text. The vacant region in the hydrophobic binding pocket is shown. Note the lack of density for solvent molecules in this region. We suggest that this vacancy allows virion uncoating, hence the limited activity of SDZ 880-061 during stages post-adsorption.

Figure 3.
Figure 3. The benzothiazine ring of SDZ 880-061 is situated between Val188 and Ile104 of VP1. These VP1 residues are displayed in CPK form to highlight the volume they occupy. There is little room for an additional carbon group on either of these residues which might be contributing to the increased activity of SDZ 880--061 against serotypes 14 and 89 (Table 6).

The above figures are reprinted by permission from Elsevier: J Mol Biol (1996, 259, 120-134) copyright 1996.