6SK6

Cryo-EM structure of rhinovirus-B5


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.20 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site.

Wald, J.Pasin, M.Richter, M.Walther, C.Mathai, N.Kirchmair, J.Makarov, V.A.Goessweiner-Mohr, N.Marlovits, T.C.Zanella, I.Real-Hohn, A.Verdaguer, N.Blaas, D.Schmidtke, M.

(2019) Proc Natl Acad Sci U S A 116: 19109-19115

  • DOI: https://doi.org/10.1073/pnas.1904732116
  • Primary Citation of Related Structures:  
    6SK5, 6SK6, 6SK7

  • PubMed Abstract: 

    Viral inhibitors, such as pleconaril and vapendavir, target conserved regions in the capsids of rhinoviruses (RVs) and enteroviruses (EVs) by binding to a hydrophobic pocket in viral capsid protein 1 (VP1). In resistant RVs and EVs, bulky residues in this pocket prevent their binding. However, recently developed pyrazolopyrimidines inhibit pleconaril-resistant RVs and EVs, and computational modeling has suggested that they also bind to the hydrophobic pocket in VP1. We studied the mechanism of inhibition of pleconaril-resistant RVs using RV-B5 (1 of the 7 naturally pleconaril-resistant rhinoviruses) and OBR-5-340, a bioavailable pyrazolopyrimidine with proven in vivo activity, and determined the 3D-structure of the protein-ligand complex to 3.6 Å with cryoelectron microscopy. Our data indicate that, similar to other capsid binders, OBR-5-340 induces thermostability and inhibits viral adsorption and uncoating. However, we found that OBR-5-340 attaches closer to the entrance of the pocket than most other capsid binders, whose viral complexes have been studied so far, showing only marginal overlaps of the attachment sites. Comparing the experimentally determined 3D structure with the control, RV-B5 incubated with solvent only and determined to 3.2 Å, revealed no gross conformational changes upon OBR-5-340 binding. The pocket of the naturally OBR-5-340-resistant RV-A89 likewise incubated with OBR-5-340 and solved to 2.9 Å was empty. Pyrazolopyrimidines have a rigid molecular scaffold and may thus be less affected by a loss of entropy upon binding. They interact with less-conserved regions than known capsid binders. Overall, pyrazolopyrimidines could be more suitable for the development of new, broadly active inhibitors.


  • Organizational Affiliation

    Centre for Structural Systems Biology (CSSB), D-22607 Hamburg, Germany.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Rhinovirus B5 VP4A [auth D]69rhinovirus B5Mutation(s): 0 
UniProt
Find proteins for Q80SQ3 (rhinovirus B5)
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Go to UniProtKB:  Q80SQ3
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UniProt GroupQ80SQ3
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Rhinovirus B5 VP2252rhinovirus B5Mutation(s): 0 
EC: 3.4.22.29 (PDB Primary Data), 3.6.1.15 (PDB Primary Data), 3.4.22.28 (PDB Primary Data), 2.7.7.48 (PDB Primary Data)
UniProt
Find proteins for B9V433 (rhinovirus B5)
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UniProt GroupB9V433
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Rhinovirus B5 VP1C [auth A]288rhinovirus B5Mutation(s): 0 
UniProt
Find proteins for Q7T659 (rhinovirus B5)
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UniProt GroupQ7T659
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Rhinovirus B5 VP3D [auth C]231rhinovirus B5Mutation(s): 0 
EC: 3.4.22.29 (PDB Primary Data), 3.6.1.15 (PDB Primary Data), 3.4.22.28 (PDB Primary Data), 2.7.7.48 (PDB Primary Data)
UniProt
Find proteins for B9V433 (rhinovirus B5)
Explore B9V433 
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UniProt GroupB9V433
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.20 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
MODEL REFINEMENTCoot0.8.9.1

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European CommissionAustria653706

Revision History  (Full details and data files)

  • Version 1.0: 2019-09-04
    Type: Initial release
  • Version 1.1: 2019-09-11
    Changes: Data collection, Database references
  • Version 1.2: 2019-09-25
    Changes: Data collection, Database references
  • Version 1.3: 2019-10-02
    Changes: Data collection, Derived calculations