Active Site Cavity of Herpesvirus Proteases Revealed by the Crystal Structure of Herpes Simplex Virus Protease/Inhibitor Complex

Hoog, Susan S.; Smith, Ward W.; Qiu, Xiayang; Janson, Cheryl A.; Hellmig, Brian D.; McQueney, Michael S.; O’Donnell, Kevin; O’Shannessy, Daniel J.; DiLella, Anthony G.; Debouck, Christine; Abdel-Meguid, Sherin S.

doi:10.1021/bi9712697

Cited by 70 publications

(67 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Diagrams of the procapsid and mature head (capsid plus internally coiled DNA) are shown at center (from Figure 1). Ribbon diagrams are shown for the φ29 scaffold (PDB code 1N04, [13 •• ]) and portal/connector (PDB code 1IJG, [9]), the HSV2 protease (PDB code IAT3, [61]), the λ accessory protein (PDB code 1TCZ, [26]) and the HK97 MCP (PDB code 1OHG, [19]). It remains to be seen whether system-to-system variation is accomplished by embellishment of the same basic fold (e.g.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…2, the 38-kDa sequence fractions matched a portion of the LETV genome containing the overlapping open reading frames corresponding to HSV-1 genes UL26 (minor capsid protein or protease) and UL26.5 (assembly or scaffolding protein). In other herpesviruses, UL26 encodes a polyprotein that is autoproteolytically cleaved to yield protease and another scaffolding protein that is distinct from the assembly or scaffolding protein encoded by UL26.5 (10,18,20). The UL26 LETV homolog is diagrammed with these putative cleavage sites ( Fig.…”

mentioning

confidence: 99%

“…3a, lane 1). On the basis of homologs of UL26 in other herpesviruses, this gene encodes a polyprotein that is autoproteolytically cleaved during expression and yields the assembly protein and protease (10,18,20). The two expressed LETV proteins likely correspond to these protein products.…”

mentioning

confidence: 99%

Identification and Expression of Immunogenic Proteins of a Disease-Associated Marine Turtle Herpesvirus

Coberley¹,

Condit²,

Herbst

et al. 2002

J Virol

View full text Add to dashboard Cite

Herpesviruses are associated with several diseases of marine turtles, including lung-eye-trachea disease (LETD) and fibropapillomatosis. Two approaches were used to identify immunodominant antigens of LETV, the LETD-associated herpesvirus. The first approach targeted glycoprotein B, which is known to be immunogenic and neutralizing in other species. The second strategy identified LETV proteins recognized on Western blots by antibodies in immune green turtle plasma. A 38-kDa protein was resolved by two-dimensional gel electrophoresis, sequenced, and identified as a scaffolding protein encoded by the overlapping open reading frames of UL26 and UL26.5. Glycoprotein B and the scaffolding protein were cloned and expressed in Escherichia coli. The expressed proteins were recognized on Western blots by antibodies in immune green turtle plasma. Phylogenetic studies based on UL26, DNA polymerase, and glycoprotein B revealed that LETV clusters with the alphaherpesviruses.Herpesviruses are associated with several diseases of marine turtles, including lung-eye-trachea disease (LETD) and fibropapillomatosis (FP). Recent efforts to understand the role of these herpesviruses and their impact on threatened and endangered marine turtle populations have focused on the development of serological assays for seroepidemiological studies. An LETD-associated herpesvirus (LETV)-specific enzyme-linked immunosorbent assay (ELISA) has been developed by using LETV-infected cell lysates as the antigen for detection of antibodies. This assay demonstrated that 21.6% of juvenile green turtles along the east coast of Florida were exposed to LETV or an LETV-like herpesvirus (3). In addition, 12 out of 13 nesting green and loggerhead turtles were shown to be seropositive for antibodies to LETV, suggesting that, as is the case with many human and mammalian herpesvirus infections, individuals are exposed at some point during their lifetimes. Clinical signs consistent with LETD have been observed in juvenile green turtles in the wild (8), and LETV has been found to be associated with LETD lesions in green turtles reared in captivity (11).LETV is a relatively low-titer and slow-growing virus. Generation of antigen for the LETV ELISA is labor intensive and subject to batch-to-batch variation. Expressed recombinant herpesvirus proteins could provide a source of antigen that would permit more extensive seroepidemiological studies of LETV infections. In this study, two strategies were used to select LETV proteins for expression. One protein was previously identified as a potential immunodominant LETV antigen (2, 3). This 38-kDa protein was recognized by many, but not all, individual wild turtles with antibodies to LETV and was targeted for cloning and expression. A second LETV protein, glycoprotein B (gB), was also selected for cloning and expression. gB has been identified as a major target of the antiherpesvirus immune response in many host species and includes virus-neutralizing activity (6,12,19). gB also has been extensively targeted for the developm...

show abstract

“…They exist in a monomer-dimer equilibrium in vitro where only the dimer is active [5][6][7]. Xray crystallographic studies on the protease from CMV, HSV1, HSV2, VZV, KSHV and EBV have shown the presence of a conserved dimer structure [8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Kinetics, inhibition and oligomerization of Epstein‐Barr virus protease

Buisson

Rivail

Hernandez³

et al. 2006

FEBS Letters

View full text Add to dashboard Cite

Epstein-Barr virus (EBV) is an omnipresent human virus causing infectious mononucleosis and EBV associated cancers. Its protease is a possible target for antiviral therapy. We studied its dimerization and enzyme kinetics with two enzyme assays based either on the release of paranitroaniline or 7-amino-4-methylcoumarin from labeled pentapeptide (Ac-KLVQA) substrates. The protease is in a monomer-dimer equilibrium where only dimers are active. In absence of citrate the K d is 20 lM and drops to 0.2 lM in presence of 0.5 M citrate. Citrate increases additionally the activity of the catalytic sites. The inhibitory constants of different substrate derived peptides and a-keto-amide based inhibitors, which have at best a K i of 4 lM, have also been evaluated.

show abstract

Active Site Cavity of Herpesvirus Proteases Revealed by the Crystal Structure of Herpes Simplex Virus Protease/Inhibitor Complex

Cited by 70 publications

References 26 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

Identification and Expression of Immunogenic Proteins of a Disease-Associated Marine Turtle Herpesvirus

Kinetics, inhibition and oligomerization of Epstein‐Barr virus protease

Contact Info

Product

Resources

About