Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site.
Journal, issue, pages	Proc Natl Acad Sci U S A, Vol. 116, Issue 38, Page 19109-19115, Year 2019
Publish date	Sep 17, 2019
Authors	Jiri Wald / Marion Pasin / Martina Richter / Christin Walther / Neann Mathai / Johannes Kirchmair / Vadim A Makarov / Nikolaus Goessweiner-Mohr / Thomas C Marlovits / Irene Zanella / Antonio Real-Hohn / Nuria Verdaguer / Dieter Blaas / Michaela Schmidtke /
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 ...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.
External links	Proc Natl Acad Sci U S A / PubMed:31462495 / PubMed Central
Methods	EM (single particle)
Resolution	2.9 - 3.6 Å
Structure data	10220 6sk5 EMDB-10220, PDB-6sk5: Cryo-EM structure of rhinovirus-B5 complexed to antiviral OBR-5-340 Method: EM (single particle) / Resolution: 3.6 Å 10221 6sk6 EMDB-10221, PDB-6sk6: Cryo-EM structure of rhinovirus-B5 Method: EM (single particle) / Resolution: 3.2 Å 10222 6sk7 EMDB-10222, PDB-6sk7: Cryo-EM structure of rhinovirus-A89 Method: EM (single particle) / Resolution: 2.9 Å
Chemicals	ChemComp-LGQ: 6-phenyl-~{N}3-[4-(trifluoromethyl)phenyl]-1~{H}-pyrazolo[3,4-d]pyrimidine-3,4-diamine
Source	human rhinovirus b5 human rhinovirus a serotype 89 (strain 41467-gallo)
Keywords	VIRUS / RV-A89 / HRV-B5 / capsid protein