The Herpesvirus Proteases as Targets for Antiviral Chemotherapy

Waxman, Lloyd; Darke, Paul L.

doi:10.1177/095632020001100101

Cited by 117 publications

(93 citation statements)

References 113 publications

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“…As yet, there are no high-resolution structures for bacteriophage proteases, but there are several for herpesvirus proteases (e.g. [24]), which are likely to be structurally similar [25 …”

Section: Expression Strategies: In Pieces or As Polyproteins?mentioning

confidence: 99%

Virus maturation: dynamics and mechanism of a stabilizing structural transition that leads to infectivity

Steven

Heymann

Cheng

et al. 2005

Current Opinion in Structural Biology

160

143

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For many viruses, the final stage of assembly involves structural transitions that convert an innocuous precursor particle into an infectious agent. This process -maturation -is controlled by proteases that trigger large-scale conformational changes. In this context, protease inhibitor antiviral drugs act by blocking maturation. Recent work has succeeded in determining the folds of representative examples of the five major proteins -major capsid protein, scaffolding protein, portal, protease and accessory protein -that are typically involved in capsid assembly. These data provide a framework for detailed mechanistic investigations and elucidation of mutations that affect assembly in various ways. The nature of the conformational change has been elucidated: it entails rigid-body rotations and translations of the arrayed subunits that transfer the interactions between them to different molecular surfaces, accompanied by refolding and redeployment of local motifs. Moreover, it has been possible to visualize maturation at the submolecular level in movies based on time-resolved cryo-electron microscopy.

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“…As yet, there are no high-resolution structures for bacteriophage proteases, but there are several for herpesvirus proteases (e.g. [24]), which are likely to be structurally similar [25 …”

Section: Expression Strategies: In Pieces or As Polyproteins?mentioning

confidence: 99%

Virus maturation: dynamics and mechanism of a stabilizing structural transition that leads to infectivity

Steven

Heymann

Cheng

et al. 2005

Current Opinion in Structural Biology

160

143

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mentioning

confidence: 99%

Cytomegalovirus Assemblin (pUL80a): Cleavage at Internal Site Not Essential for Virus Growth; Proteinase Absent from Virions

Chan

Brignole

Gibson

2002

J Virol

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Herpesviruses encode a proteinase that functions during assembly and maturation of the capsid and that is essential for the production of infectious virus (13,17,24,31,41,42,53,55). The human cytomegalovirus (HCMV) homolog is synthesized as an enzymatically active 74-kDa precursor that cleaves itself at two consensus sequences called the maturational (M) and release (R) sites (Fig. 1), which have counterparts among all herpesviruses (1,12,20,55). M-site cleavage of the HCMV precursor eliminates its 6-kDa carboxyl "tail," which mediates interaction with the major capsid protein (MCP; pUL86) at the earliest stages of subunit organization and capsid assembly (2, 37, 56). R-site cleavage releases the 28-kDa amino proteolytic domain from the carboxyl portion of the precursor, which targets the proteinase to its site of action within nascent intranuclear capsids (30,39,55,56). The crystal structure of the proteolytic domain, called assemblin, established it as the prototype of a new clan of serine proteinases, distinguished by their Ser-His-His (rather than Ser-His-Asp/Glu) catalytic triad and different protein folds (7,43,46,51). Assemblin is activated by dimerization (8,9,32) to constitute an enzyme with two separate catalytic sites and poor catalytic efficiency compared to other serine proteinases (38,44,48,50,53).In addition to the M and R sites common to the herpesvirus group, the HCMV proteinase has internal (I) and cryptic (C) cleavage sites within assemblin ( Fig. 1) (1, 5, 28, 54). The I site has a recognized consensus sequence among other cytomegalovirus (CMV) homologs and has received comparatively more attention than the C site, which may be restricted to HCMV. The I site is located near the middle of assemblin, between Ser132 and His157 of the catalytic triad, yet its cleavage has no detected effect on the proteolytic behavior of the enzyme (22,25,28,36), in contrast to the inactivating D-site cleavage of the Kaposi's sarcoma herpesvirus, human herpesvirus 8 (40). Furthermore, enzymatic activity can be constituted by coexpressing the separately cloned coding sequences for the two I-site cleavage fragments, A n and A c (22, 23), or by combining the independently expressed fragments in vitro (36). Moreover, an enzymatically active form of the herpes simplex virus (HSV) assemblin homolog, which has no I site, can be constituted by coexpressing the HSV sequences that are counterparts to CMV A n and A c (21). Thus, the significance of I-site cleavage has not been revealed by studies of the cloned enzyme expressed and tested in the absence of other viral proteins. The work described here was done to test the requirement for I-site cleavage in the context of virus-infected cells by constructing and studying a mutant HCMV encoding a defective I site. Phenotypic characterizations were done to compare the I-site mutant and wild-type virus with respect to cytopathic effect (CPE), yield of infectious virus and noninfectious extracellular particles, I-site cleavage, and incorporation of the proteinase into virus parti...

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“…The dimer is weakly associated with dissociation constants (K D ) in the micromolar range [79]. It is the active species, while the monomer is almost inactive.…”

Section: Regulation Of Activitymentioning

confidence: 99%

“…It is the active species, while the monomer is almost inactive. The equilibrium is shifted towards the dimer by higher concentrations of assemblin, salts and co-solvents like glycerol [37,75,79]. Dimerization induces refolding of a loop (residues 162 to 171) near the active site.…”

Section: Regulation Of Activitymentioning

confidence: 99%

Assemblins as maturational proteases in herpesviruses

Zühlsdorf

Hinrichs

2017

Journal of General Virology

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During assembly of herpesvirus capsids, a protein scaffold self-assembles to ring-like structures forming the scaffold of the spherical procapsids. Proteolytic activity of the herpesvirus maturational protease causes structural changes that result in angularization of the capsids. In those mature icosahedral capsids, the packaging of viral DNA into the capsids can take place. The strictly regulated protease is called assemblin. It is inactive in its monomeric state and activated by dimerization. The structures of the dimeric forms of several assemblins from all herpesvirus subfamilies have been elucidated in the last two decades. They revealed a unique serine-protease fold with a catalytic triad consisting of a serine and two histidines. Inhibitors that disturb dimerization by binding to the dimerization area were found recently. Additionally, the structure of the monomeric form of assemblin from pseudorabies virus and some monomer-like structures of Kaposi's sarcoma-associated herpesvirus assemblin were solved. These findings are the proof-of-principle for the development of new anti-herpesvirus drugs. Therefore, the most important information on this fascinating and unique class of proteases is summarized here.

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The Herpesvirus Proteases as Targets for Antiviral Chemotherapy

Cited by 117 publications

References 113 publications

Virus maturation: dynamics and mechanism of a stabilizing structural transition that leads to infectivity

Virus maturation: dynamics and mechanism of a stabilizing structural transition that leads to infectivity

Cytomegalovirus Assemblin (pUL80a): Cleavage at Internal Site Not Essential for Virus Growth; Proteinase Absent from Virions

Assemblins as maturational proteases in herpesviruses

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