PDBsum entry 4cdq

Virus

PDB id: 4cdq

Contents

Protein chains

297 a.a.

245 a.a.

242 a.a.

58 a.a.

Ligands

7VR

Metals

_NA

Waters ×102

PDB id:

4cdq

Name:

Virus

Title:

Crystal structure of human enterovirus 71 in complex with the uncoating inhibitor gpp2

Structure:

Vp1. Chain: a. Engineered: yes. Vp2. Chain: b. Engineered: yes. Vp3. Chain: c. Engineered: yes.

Source:

Enterovirus a71. Organism_taxid: 39054. Expressed in: chlorocebus aethiops. Expression_system_taxid: 9534. Expression_system_cell_line: vero cells. Expression_system_cell_line: vero cells

Resolution:

2.65Å R-factor: 0.245 R-free: 0.246

Authors:

L.Decolibus,X.Wang,J.A.B.Spyrou,J.Kelly,J.Ren,J.Grimes,G.Puerstinger, N.Stonehouse,T.S.Walter,Z.Hu,J.Wang,X.Li,W.Peng,D.Rowlands,E.E.Fry, Z.Rao,D.I.Stuart

Key ref:

L.De Colibus et al. (2014). More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules. Nat Struct Biol, 21, 282-288. PubMed id: 24509833 DOI: 10.1038/nsmb.2769

Date:

05-Nov-13 Release date: 12-Feb-14

Protein chain

B2ZUN0  (B2ZUN0_HE71) -  Genome polyprotein from Human enterovirus 71

Seq: 2193 a.a.

Struc: 297 a.a.

Protein chain

B2ZUN0  (B2ZUN0_HE71) -  Genome polyprotein from Human enterovirus 71

Seq: 2193 a.a.

Struc: 245 a.a.

Protein chain

B2ZUN0  (B2ZUN0_HE71) -  Genome polyprotein from Human enterovirus 71

Seq: 2193 a.a.

Struc: 242 a.a.

Protein chain

B2ZUN0  (B2ZUN0_HE71) -  Genome polyprotein from Human enterovirus 71

Seq: 2193 a.a.

Struc: 58 a.a.

Enzyme reactions

• Enzyme class 2: Chains A, B, C, D: 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 A, B, C, D: 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 A, B, C, D: 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 A, B, C, D: 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: 10.1038/nsmb.2769

Nat Struct Biol 21:282-288 (2014)

PubMed id: 24509833

More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules.

L.De Colibus, X.Wang, J.A.Spyrou, J.Kelly, J.Ren, J.Grimes, G.Puerstinger, N.Stonehouse, T.S.Walter, Z.Hu, J.Wang, X.Li, W.Peng, D.J.Rowlands, E.E.Fry, Z.Rao, D.I.Stuart.

ABSTRACT

Enterovirus 71 (HEV71) epidemics in children and infants result mainly in mild symptoms; however, especially in the Asia-Pacific region, infection can be fatal. At present, no therapies are available. We have used structural analysis of the complete virus to guide the design of HEV71 inhibitors. Analysis of complexes with four 3-(4-pyridyl)-2-imidazolidinone derivatives with varying anti-HEV71 activities pinpointed key structure-activity correlates. We then identified additional potentially beneficial substitutions, developed methods to reliably triage compounds by quantum mechanics-enhanced ligand docking and synthesized two candidates. Structural analysis and in vitro assays confirmed the predicted binding modes and their ability to block viral infection. One ligand (with IC50 of 25 pM) is an order of magnitude more potent than the best previously reported inhibitor and is also more soluble. Our approach may be useful in the design of effective drugs for enterovirus infections.