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Article: Mechanism of enterovirus VP0 maturation cleavage based on the structure of a stabilised assembly intermediate.

Kingston, Natalie J / Snowden, Joseph S / Grehan, Keith / Hall, Philippa K / Hietanen, Eero V / Passchier, Tim C / Polyak, Stephen J / Filman, David J / Hogle, James M / Rowlands, David J / Stonehouse, Nicola J

bioRxiv : the preprint server for biology

2024

Abstract: Molecular details of genome packaging are little understood for the majority of viruses. In enteroviruses (EVs), cleavage of the structural protein VP0 into VP4 and VP2 is initiated by the incorporation of RNA into the assembling virion and is essential ... ...

Abstract	Molecular details of genome packaging are little understood for the majority of viruses. In enteroviruses (EVs), cleavage of the structural protein VP0 into VP4 and VP2 is initiated by the incorporation of RNA into the assembling virion and is essential for infectivity. We have applied a combination of bioinformatic, molecular and structural approaches to generate the first high-resolution structure of an intermediate in the assembly pathway, termed a provirion, which contains RNA and intact VP0. We have demonstrated an essential role of VP0 E096 in VP0 cleavage independent of RNA encapsidation and generated a new model of capsid maturation, supported by bioinformatic analysis. This provides a molecular basis for RNA-dependence, where RNA induces conformational changes required for VP0 maturation, but that RNA packaging itself is not sufficient to induce maturation. These data have implications for understanding production of infectious virions and potential relevance for future vaccine and antiviral drug design.
Language	English
Publishing date	2024-04-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.06.588229
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Article ; Online: A 3D framework for understanding enterovirus 71.

Hogle, James M

Nature structural & molecular biology

2012 Volume 19, Issue 4, Page(s) 367–368

Abstract: Two papers report the structure of the virion of emerging pathogen EV71, providing a three-dimensional context for understanding many of its biological functions. ...

Abstract	Two papers report the structure of the virion of emerging pathogen EV71, providing a three-dimensional context for understanding many of its biological functions.
MeSH term(s)	Enterovirus A, Human/chemistry ; Enterovirus Infections/virology ; Humans ; Virion/chemistry
Language	English
Publishing date	2012-04-04
Publishing country	United States
Document type	News ; Comment
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/nsmb.2276
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Article ; Online: Real-Time Imaging of Polioviral RNA Translocation across a Membrane.

Karunatilaka, Krishanthi S / Filman, David J / Strauss, Mike / Loparo, Joseph J / Hogle, James M

mBio

2021 Volume 12, Issue 1

Abstract: Genome transfer from a virus into a cell is a critical early step in viral replication. Enveloped viruses achieve the delivery of their genomes into the cytoplasm by merging the viral membrane with the cellular membrane via a conceptually simple ... ...

Abstract	Genome transfer from a virus into a cell is a critical early step in viral replication. Enveloped viruses achieve the delivery of their genomes into the cytoplasm by merging the viral membrane with the cellular membrane via a conceptually simple mechanism called membrane fusion. In contrast, genome translocation mechanisms in nonenveloped viruses, which lack viral membranes, remain poorly understood. Although cellular assays provide useful information about cell entry and genome release, it is difficult to obtain detailed mechanistic insights due both to the inherent technical difficulties associated with direct visualization of these processes and to the prevalence of nonproductive events in cellular assays performed at a very high multiplicity of infection. To overcome these issues, we developed an
MeSH term(s)	Capsid Proteins/genetics ; Capsid Proteins/metabolism ; Computer Systems ; Genome, Viral/physiology ; HeLa Cells ; Host Microbial Interactions/physiology ; Humans ; In Vitro Techniques ; Liposomes/metabolism ; Optical Imaging/methods ; Poliovirus/genetics ; Poliovirus/physiology ; RNA, Viral/metabolism ; Virus Internalization
Chemical Substances	Capsid Proteins ; Liposomes ; RNA, Viral
Language	English
Publishing date	2021-02-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.03695-20
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Article ; Online: Resistance to a Nucleoside Analog Antiviral Drug from More Rapid Extension of Drug-Containing Primers.

Chen, Han / Lawler, Jessica L / Filman, David J / Hogle, James M / Coen, Donald M

mBio

2021 Volume 12, Issue 1

Abstract: Nucleoside analogs are mainstays of antiviral therapy. Although resistance to these drugs hinders their use, understanding resistance can illuminate mechanisms of the drugs and their targets. Certain nucleoside analogs, such as ganciclovir (GCV), a ... ...

Abstract	Nucleoside analogs are mainstays of antiviral therapy. Although resistance to these drugs hinders their use, understanding resistance can illuminate mechanisms of the drugs and their targets. Certain nucleoside analogs, such as ganciclovir (GCV), a leading therapy for human cytomegalovirus (HCMV), contain the equivalent of a 3'-hydoxyl moiety, yet their triphosphates can terminate genome synthesis (nonobligate chain termination). For ganciclovir, chain termination is delayed until incorporation of the subsequent nucleotide, after which viral polymerase idling (repeated addition and removal of incorporated nucleotides) prevents extension. Here, we investigated how an alanine-to-glycine substitution at residue 987 (A987G), in conserved motif V in the thumb subdomain of the catalytic subunit (Pol) of HCMV DNA polymerase, affects polymerase function to overcome delayed chain termination and confer ganciclovir resistance. Steady-state enzyme kinetic studies revealed no effects of this substitution on incorporation of ganciclovir-triphosphate into DNA that could explain resistance. We also found no effects of the substitution on Pol's exonuclease activity, and the mutant enzyme still exhibited idling after incorporation of GCV and the subsequent nucleotide. However, despite extending normal DNA primers similarly to wild-type enzyme, A987G Pol more rapidly extended ganciclovir-containing DNA primers, thereby overcoming chain termination. The mutant Pol also more rapidly extended RNA primers, a previously unreported activity for HCMV Pol. Structural analysis of related Pols bound to primer-templates provides a rationale for these results. These studies uncover a new drug resistance mechanism, potentially applicable to other nonobligate chain-terminating nucleoside analogs, and shed light on polymerase functions.
MeSH term(s)	Amino Acid Substitution ; Antiviral Agents/pharmacology ; Cytomegalovirus/drug effects ; Cytomegalovirus/enzymology ; Cytomegalovirus/genetics ; DNA Primers/genetics ; DNA, Viral/genetics ; DNA-Directed DNA Polymerase/chemistry ; DNA-Directed DNA Polymerase/genetics ; DNA-Directed DNA Polymerase/metabolism ; Drug Resistance, Viral/genetics ; Humans ; Kinetics ; Nucleosides/pharmacology
Chemical Substances	Antiviral Agents ; DNA Primers ; DNA, Viral ; Nucleosides ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
Language	English
Publishing date	2021-02-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.03492-20
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Article: Production of antigenically stable enterovirus A71 virus-like particles in

Kingston, Natalie J / Snowden, Joseph S / Martyna, Agnieszka / Shegdar, Mona / Grehan, Keith / Tedcastle, Alison / Pegg, Elaine / Fox, Helen / Macadam, Andrew J / Martin, Javier / Hogle, James M / Rowlands, David J / Stonehouse, Nicola J

bioRxiv : the preprint server for biology

2023

Abstract: Enterovirus A71 (EVA71) causes widespread disease in young children with occasional fatal consequences. In common with other picornaviruses, both empty capsids (ECs) and infectious virions are produced during the viral lifecycle. While initially ... ...

Abstract	Enterovirus A71 (EVA71) causes widespread disease in young children with occasional fatal consequences. In common with other picornaviruses, both empty capsids (ECs) and infectious virions are produced during the viral lifecycle. While initially antigenically indistinguishable from virions, ECs readily convert to an expanded conformation at moderate temperatures. In the closely related poliovirus, these conformational changes result in loss of antigenic sites required to elicit protective immune responses. Whether this is true for EVA71 remains to be determined and is the subject of this investigation. We previously reported the selection of a thermally resistant EVA71 genogroup B2 population using successive rounds of heating and passage. The mutations found in the structural protein-coding region of the selected population conferred increased thermal stability to both virions and naturally produced ECs. Here, we introduced these mutations into a recombinant expression system to produce stabilised virus-like particles (VLPs) in
Language	English
Publishing date	2023-02-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.30.526315
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Article ; Online: Production of antigenically stable enterovirus A71 virus-like particles in

The Journal of general virology

2023 Volume 104, Issue 6

Abstract	Enterovirus A71 (EVA71) causes widespread disease in young children with occasional fatal consequences. In common with other picornaviruses, both empty capsids (ECs) and infectious virions are produced during the viral lifecycle. While initially antigenically indistinguishable from virions, ECs readily convert to an expanded conformation at moderate temperatures. In the closely related poliovirus, these conformational changes result in loss of antigenic sites required to elicit protective immune responses. Whether this is true for EVA71 remains to be determined and is the subject of this investigation.We previously reported the selection of a thermally resistant EVA71 genogroup B2 population using successive rounds of heating and passage. The mutations found in the structural protein-coding region of the selected population conferred increased thermal stability to both virions and naturally produced ECs. Here, we introduced these mutations into a recombinant expression system to produce stabilized virus-like particles (VLPs) in
MeSH term(s)	Child ; Humans ; Child, Preschool ; Enterovirus ; Enterovirus Infections ; Antigens, Viral/genetics ; Vaccines ; Poliovirus/genetics ; Antibodies, Viral
Chemical Substances	Antigens, Viral ; Vaccines ; Antibodies, Viral
Language	English
Publishing date	2023-06-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/jgv.0.001867
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Article ; Online: A small molecule exerts selective antiviral activity by targeting the human cytomegalovirus nuclear egress complex.

Chen, Han / Lye, Ming F / Gorgulla, Christoph / Ficarro, Scott B / Cuny, Gregory D / Scott, David A / Wu, Fan / Rothlauf, Paul W / Wang, Xiaoou / Fernandez, Rosio / Pesola, Jean M / Draga, Sorin / Marto, Jarrod A / Hogle, James M / Arthanari, Haribabu / Coen, Donald M

PLoS pathogens

2023 Volume 19, Issue 11, Page(s) e1011781

Abstract: Human cytomegalovirus (HCMV) is an important pathogen for which new antiviral drugs are needed. HCMV, like other herpesviruses, encodes a nuclear egress complex (NEC) composed of two subunits, UL50 and UL53, whose interaction is crucial for viral ... ...

Abstract	Human cytomegalovirus (HCMV) is an important pathogen for which new antiviral drugs are needed. HCMV, like other herpesviruses, encodes a nuclear egress complex (NEC) composed of two subunits, UL50 and UL53, whose interaction is crucial for viral replication. To explore whether small molecules can exert selective antiviral activity by inhibiting NEC subunit interactions, we established a homogeneous time-resolved fluorescence (HTRF) assay of these interactions and used it to screen >200,000 compound-containing wells. Two compounds, designated GK1 and GK2, which selectively inhibited this interaction in the HTRF assay with GK1 also active in a co-immunoprecipitation assay, exhibited more potent anti-HCMV activity than cytotoxicity or activity against another herpesvirus. At doses that substantially reduced HCMV plaque formation, GK1 and GK2 had little or no effect on the expression of viral proteins and reduced the co-localization of UL53 with UL50 at the nuclear rim in a subset of cells. GK1 and GK2 contain an acrylamide moiety predicted to covalently interact with cysteines, and an analog without this potential lacked activity. Mass spectrometric analysis showed binding of GK2 to multiple cysteines on UL50 and UL53. Nevertheless, substitution of cysteine 214 of UL53 with serine (C214S) ablated detectable inhibitory activity of GK1 and GK2 in vitro, and the C214S substitution engineered into HCMV conferred resistance to GK1, the more potent of the two inhibitors. Thus, GK1 exerts selective antiviral activity by targeting the NEC. Docking studies suggest that the acrylamide tethers one end of GK1 or GK2 to C214 within a pocket of UL53, permitting the other end of the molecule to sterically hinder UL50 to prevent NEC formation. Our results prove the concept that targeting the NEC with small molecules can selectively block HCMV replication. Such compounds could serve as a foundation for development of anti-HCMV drugs and as chemical tools for studying HCMV.
MeSH term(s)	Humans ; Cytomegalovirus ; Cell Nucleus/metabolism ; Herpesviridae/metabolism ; Virus Replication ; Simplexvirus ; Acrylamides/metabolism ; Antiviral Agents/pharmacology ; Antiviral Agents/metabolism
Chemical Substances	Acrylamides ; Antiviral Agents
Language	English
Publishing date	2023-11-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011781
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Article ; Online: Cryo-EM structures reveal two distinct conformational states in a picornavirus cell entry intermediate.

Shah, Pranav N M / Filman, David J / Karunatilaka, Krishanthi S / Hesketh, Emma L / Groppelli, Elisabetta / Strauss, Mike / Hogle, James M

PLoS pathogens

2020 Volume 16, Issue 9, Page(s) e1008920

Abstract: The virions of enteroviruses such as poliovirus undergo a global conformational change after binding to the cellular receptor, characterized by a 4% expansion, and by the opening of holes at the two and quasi-three-fold symmetry axes of the capsid. The ... ...

Abstract	The virions of enteroviruses such as poliovirus undergo a global conformational change after binding to the cellular receptor, characterized by a 4% expansion, and by the opening of holes at the two and quasi-three-fold symmetry axes of the capsid. The resultant particle is called a 135S particle or A-particle and is thought to be on the pathway to a productive infection. Previously published studies have concluded that the membrane-interactive peptides, namely VP4 and the N-terminus of VP1, are irreversibly externalized in the 135S particle. However, using established protocols to produce the 135S particle, and single particle cryo-electron microscopy methods, we have identified at least two unique states that we call the early and late 135S particle. Surprisingly, only in the "late" 135S particles have detectable levels of the VP1 N-terminus been trapped outside the capsid. Moreover, we observe a distinct density inside the capsid that can be accounted for by VP4 that remains associated with the genome. Taken together our results conclusively demonstrate that the 135S particle is not a unique conformation, but rather a family of conformations that could exist simultaneously.
MeSH term(s)	Capsid/metabolism ; Capsid/ultrastructure ; Capsid Proteins/metabolism ; Cryoelectron Microscopy ; Humans ; Models, Molecular ; Poliomyelitis/metabolism ; RNA, Viral/metabolism ; RNA, Viral/ultrastructure ; Receptors, Virus/metabolism ; Virion/metabolism ; Virion/ultrastructure ; Virus Internalization
Chemical Substances	Capsid Proteins ; RNA, Viral ; Receptors, Virus
Language	English
Publishing date	2020-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1008920
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Article ; Online: DNA-Corralled Nanodiscs for the Structural and Functional Characterization of Membrane Proteins and Viral Entry.

Zhao, Zhao / Zhang, Meng / Hogle, James M / Shih, William M / Wagner, Gerhard / Nasr, Mahmoud L

Journal of the American Chemical Society

2018 Volume 140, Issue 34, Page(s) 10639–10643

Abstract: Here we present a modular method for manufacturing large-sized nanodiscs using DNA-origami barrels as scaffolding corrals. Large-sized nanodiscs can be produced by first decorating the inside of DNA barrels with small lipid-bilayer nanodiscs, which open ... ...

Abstract	Here we present a modular method for manufacturing large-sized nanodiscs using DNA-origami barrels as scaffolding corrals. Large-sized nanodiscs can be produced by first decorating the inside of DNA barrels with small lipid-bilayer nanodiscs, which open up when adding extra lipid to form large nanodiscs of diameters ∼45 or ∼70 nm as prescribed by the enclosing barrel dimension. Densely packed membrane protein arrays are then reconstituted within these large nanodiscs for potential structure determination. Furthermore, we demonstrate the potential of these nanodiscs as model membranes to study poliovirus entry.
MeSH term(s)	Cholesterol/chemistry ; DNA/chemistry ; Humans ; Lipid Bilayers/chemistry ; Membrane Proteins/chemistry ; Nanostructures/chemistry ; Nucleic Acid Conformation ; Particle Size ; Phosphatidylcholines/chemistry ; Phosphatidylglycerols/chemistry ; Photosynthetic Reaction Center Complex Proteins/chemistry ; Poliovirus/physiology ; Receptors, Virus/chemistry ; Rhodobacter sphaeroides/chemistry ; Virus Internalization ; Voltage-Dependent Anion Channel 1/chemistry
Chemical Substances	Lipid Bilayers ; Membrane Proteins ; Phosphatidylcholines ; Phosphatidylglycerols ; Photosynthetic Reaction Center Complex Proteins ; Receptors, Virus ; VDAC1 protein, human ; poliovirus receptor ; 1-palmitoyl-2-oleoylglycero-3-phosphoglycerol (81490-05-3) ; DNA (9007-49-2) ; Cholesterol (97C5T2UQ7J) ; Voltage-Dependent Anion Channel 1 (EC 1.6.-) ; 1-palmitoyl-2-oleoylphosphatidylcholine (TE895536Y5)
Language	English
Publishing date	2018-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.8b04638
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Article ; Online: A small molecule exerts selective antiviral activity by targeting the human cytomegalovirus nuclear egress complex.

Han Chen / Ming F Lye / Christoph Gorgulla / Scott B Ficarro / Gregory D Cuny / David A Scott / Fan Wu / Paul W Rothlauf / Xiaoou Wang / Rosio Fernandez / Jean M Pesola / Sorin Draga / Jarrod A Marto / James M Hogle / Haribabu Arthanari / Donald M Coen

PLoS Pathogens, Vol 19, Iss 11, p e

2023 Volume 1011781

Abstract	Human cytomegalovirus (HCMV) is an important pathogen for which new antiviral drugs are needed. HCMV, like other herpesviruses, encodes a nuclear egress complex (NEC) composed of two subunits, UL50 and UL53, whose interaction is crucial for viral replication. To explore whether small molecules can exert selective antiviral activity by inhibiting NEC subunit interactions, we established a homogeneous time-resolved fluorescence (HTRF) assay of these interactions and used it to screen >200,000 compound-containing wells. Two compounds, designated GK1 and GK2, which selectively inhibited this interaction in the HTRF assay with GK1 also active in a co-immunoprecipitation assay, exhibited more potent anti-HCMV activity than cytotoxicity or activity against another herpesvirus. At doses that substantially reduced HCMV plaque formation, GK1 and GK2 had little or no effect on the expression of viral proteins and reduced the co-localization of UL53 with UL50 at the nuclear rim in a subset of cells. GK1 and GK2 contain an acrylamide moiety predicted to covalently interact with cysteines, and an analog without this potential lacked activity. Mass spectrometric analysis showed binding of GK2 to multiple cysteines on UL50 and UL53. Nevertheless, substitution of cysteine 214 of UL53 with serine (C214S) ablated detectable inhibitory activity of GK1 and GK2 in vitro, and the C214S substitution engineered into HCMV conferred resistance to GK1, the more potent of the two inhibitors. Thus, GK1 exerts selective antiviral activity by targeting the NEC. Docking studies suggest that the acrylamide tethers one end of GK1 or GK2 to C214 within a pocket of UL53, permitting the other end of the molecule to sterically hinder UL50 to prevent NEC formation. Our results prove the concept that targeting the NEC with small molecules can selectively block HCMV replication. Such compounds could serve as a foundation for development of anti-HCMV drugs and as chemical tools for studying HCMV.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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