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

J 2019

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

WALD, Jiri, Marion PASIN, Martina RICHTER, Christin WALTHER, Neann MATHAI et. al.

Basic information

Original name

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

Authors

Edition

Proceedings of the National Academy of Sciences of the United States of America, WASHINGTON, National Academy of Sciences, 2019, 0027-8424

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10607 Virology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 9.412

DOI

http://dx.doi.org/10.1073/pnas.1904732116

UT WoS

000486388400057

Keywords in English

rhinovirus; capsid binder; inhibitor; 3D structure; cryo-EM

Abstract

V originále

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 angstrom 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 angstrom, 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 angstrom 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.

Links

90043, large research infrastructures

Name: CIISB

Citovat

WALD, Jiri, 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 and Michaela SCHMIDTKE. Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site. Proceedings of the National Academy of Sciences of the United States of America. WASHINGTON: National Academy of Sciences, 2019, vol. 116, No 38, p. 19109-19115. ISSN 0027-8424. Available from: https://dx.doi.org/10.1073/pnas.1904732116.

@article{2409587,
   author = {Wald, Jiri and Pasin, Marion and Richter, Martina and Walther, Christin and Mathai, Neann and Kirchmair, Johannes and Makarov, Vadim A and GoessweinerandMohr, Nikolaus and Marlovits, Thomas C and Zanella, Irene and RealandHohn, Antonio and Verdaguer, Nuria and Blaas, Dieter and Schmidtke, Michaela},
   article_location = {WASHINGTON},
   article_number = {38},
   doi = {http://dx.doi.org/10.1073/pnas.1904732116},
   keywords = {rhinovirus; capsid binder; inhibitor; 3D structure; cryo-EM},
   language = {eng},
   issn = {0027-8424},
   journal = {Proceedings of the National Academy of Sciences of the United States of America},
   title = {Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site},
   url = {https://www.pnas.org/doi/full/10.1073/pnas.1904732116},
   volume = {116},
   year = {2019}
}

TY  - JOUR
ID  - 2409587
AU  - Wald, Jiri - Pasin, Marion - Richter, Martina - Walther, Christin - Mathai, Neann - Kirchmair, Johannes - Makarov, Vadim A - Goessweiner-Mohr, Nikolaus - Marlovits, Thomas C - Zanella, Irene - Real-Hohn, Antonio - Verdaguer, Nuria - Blaas, Dieter - Schmidtke, Michaela
PY  - 2019
TI  - Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site
JF  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 116
IS  - 38
SP  - 19109-19115
EP  - 19109-19115
PB  - National Academy of Sciences
SN  - 00278424
KW  - rhinovirus
KW  - capsid binder
KW  - inhibitor
KW  - 3D structure
KW  - cryo-EM
UR  - https://www.pnas.org/doi/full/10.1073/pnas.1904732116
N2  - 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 angstrom 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 angstrom, 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 angstrom 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.
ER  -

WALD, Jiri, 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 and Michaela SCHMIDTKE. Cryo-EM structure of pleconaril-resistant rhinovirus-B5 complexed to the antiviral OBR-5-340 reveals unexpected binding site. \textit{Proceedings of the National Academy of Sciences of the United States of America}. WASHINGTON: National Academy of Sciences, 2019, vol.~116, No~38, p.~19109-19115. ISSN~0027-8424. Available from: https://dx.doi.org/10.1073/pnas.1904732116.

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