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Title: Serotype-Specific Structural Differences in the Protease-Cofactor Complexes of the Dengue Virus Family

Abstract

With an estimated 40% of the world population at risk, dengue poses a significant threat to human health, especially in tropical and subtropical regions. Preventative and curative efforts, such as vaccine development and drug discovery, face additional challenges due to the occurrence of four antigenically distinct serotypes of the causative dengue virus (DEN1 to -4). Complex immune responses resulting from repeat assaults by the different serotypes necessitate simultaneous targeting of all forms of the virus. One of the promising targets for drug development is the highly conserved two-component viral protease NS2B-NS3, which plays an essential role in viral replication by processing the viral precursor polyprotein into functional proteins. In this paper, we report the 2.1-{angstrom} crystal structure of the DEN1 NS2B hydrophilic core (residues 49 to 95) in complex with the NS3 protease domain (residues 1 to 186) carrying an internal deletion in the N terminus (residues 11 to 20). While the overall folds within the protease core are similar to those of DEN2 and DEN4 proteases, the conformation of the cofactor NS2B is dramatically different from those of other flaviviral apoprotease structures. The differences are especially apparent within its C-terminal region, implicated in substrate binding. The structure reveals formore » the first time serotype-specific structural elements in the dengue virus family, with the reported alternate conformation resulting from a unique metal-binding site within the DEN1 sequence. We also report the identification of a 10-residue stretch within NS3pro that separates the substrate-binding function from the catalytic turnover rate of the enzyme. Implications for broad-spectrum drug discovery are discussed.« less

Authors:
; ; ; ; ;  [1]
  1. Scripps
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002282
Resource Type:
Journal Article
Journal Name:
J. Virol.
Additional Journal Information:
Journal Volume: 84; Journal Issue: (6) ; 03, 2010; Journal ID: ISSN 0022-538X
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; FUNCTIONALS; PRECURSOR; PROCESSING; PROTEINS; RESIDUES; SUBSTRATES; TARGETS; VACCINES

Citation Formats

Chandramouli, Sumana, Joseph, Jeremiah S, Daudenarde, Sophie, Gatchalian, Jovylyn, Cornillez-Ty, Cromwell, and Kuhn, Peter. Serotype-Specific Structural Differences in the Protease-Cofactor Complexes of the Dengue Virus Family. United States: N. p., 2010. Web. doi:10.1128/JVI.02044-09.
Chandramouli, Sumana, Joseph, Jeremiah S, Daudenarde, Sophie, Gatchalian, Jovylyn, Cornillez-Ty, Cromwell, & Kuhn, Peter. Serotype-Specific Structural Differences in the Protease-Cofactor Complexes of the Dengue Virus Family. United States. https://doi.org/10.1128/JVI.02044-09
Chandramouli, Sumana, Joseph, Jeremiah S, Daudenarde, Sophie, Gatchalian, Jovylyn, Cornillez-Ty, Cromwell, and Kuhn, Peter. 2010. "Serotype-Specific Structural Differences in the Protease-Cofactor Complexes of the Dengue Virus Family". United States. https://doi.org/10.1128/JVI.02044-09.
@article{osti_1002282,
title = {Serotype-Specific Structural Differences in the Protease-Cofactor Complexes of the Dengue Virus Family},
author = {Chandramouli, Sumana and Joseph, Jeremiah S and Daudenarde, Sophie and Gatchalian, Jovylyn and Cornillez-Ty, Cromwell and Kuhn, Peter},
abstractNote = {With an estimated 40% of the world population at risk, dengue poses a significant threat to human health, especially in tropical and subtropical regions. Preventative and curative efforts, such as vaccine development and drug discovery, face additional challenges due to the occurrence of four antigenically distinct serotypes of the causative dengue virus (DEN1 to -4). Complex immune responses resulting from repeat assaults by the different serotypes necessitate simultaneous targeting of all forms of the virus. One of the promising targets for drug development is the highly conserved two-component viral protease NS2B-NS3, which plays an essential role in viral replication by processing the viral precursor polyprotein into functional proteins. In this paper, we report the 2.1-{angstrom} crystal structure of the DEN1 NS2B hydrophilic core (residues 49 to 95) in complex with the NS3 protease domain (residues 1 to 186) carrying an internal deletion in the N terminus (residues 11 to 20). While the overall folds within the protease core are similar to those of DEN2 and DEN4 proteases, the conformation of the cofactor NS2B is dramatically different from those of other flaviviral apoprotease structures. The differences are especially apparent within its C-terminal region, implicated in substrate binding. The structure reveals for the first time serotype-specific structural elements in the dengue virus family, with the reported alternate conformation resulting from a unique metal-binding site within the DEN1 sequence. We also report the identification of a 10-residue stretch within NS3pro that separates the substrate-binding function from the catalytic turnover rate of the enzyme. Implications for broad-spectrum drug discovery are discussed.},
doi = {10.1128/JVI.02044-09},
url = {https://www.osti.gov/biblio/1002282}, journal = {J. Virol.},
issn = {0022-538X},
number = (6) ; 03, 2010,
volume = 84,
place = {United States},
year = {Thu Mar 04 00:00:00 EST 2010},
month = {Thu Mar 04 00:00:00 EST 2010}
}