Ligand-bound structures of the dengue virus protease reveal the active conformation

Christian G. Noble, Cheah Chen Seh, Alexander T. Chao, Pei-Yong Shi

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

Dengue is a mosquito-borne viral hemorrhagic disease that is a major threat to human health in tropical and subtropical regions. Here we report crystal structures of a peptide covalently bound to dengue virus serotype 3 (DENV-3) protease as well as the serine-protease inhibitor aprotinin bound to the same enzyme. These structures reveal, for the first time, a catalytically active, closed conformation of the DENV protease. In the presence of the peptide, the DENV-3 protease forms the closed conformation in which the hydrophilic β-hairpin region of NS2B wraps around the NS3 protease core, in a manner analogous to the structure of West Nile virus (WNV) protease. Our results confirm that flavivirus proteases form the closed conformation during proteolysis, as previously proposed for WNV. The current DENV-3 protease structures reveal the detailed interactions at the P4= to P3 sites of the substrate. The new structural information explains the sequence preference, particularly for long basic residues in the nonprime side, as well as the difference in substrate specificity between the WNV and DENV proteases at the prime side. Structural analysis of the DENV-3 protease-peptide complex revealed a pocket that is formed by residues from NS2B and NS3; this pocket also exists in the WNV NS2B/NS3 protease structure and could be targeted for potential antivirus development. The structural information presented in the current study is invaluable for the design of specific inhibitors of DENV protease.

Original languageEnglish (US)
Pages (from-to)438-446
Number of pages9
JournalJournal of Virology
Volume86
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Fingerprint

Dengue virus
Dengue Virus
Peptide Hydrolases
proteinases
Ligands
West Nile virus
peptides
Peptides
ligands
Flavivirus
Serine Proteinase Inhibitors
Aprotinin
Dengue
dengue
Virus Diseases
Substrate Specificity
Protease Inhibitors
Culicidae
serine proteinases
substrate specificity

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Ligand-bound structures of the dengue virus protease reveal the active conformation. / Noble, Christian G.; Seh, Cheah Chen; Chao, Alexander T.; Shi, Pei-Yong.

In: Journal of Virology, Vol. 86, No. 1, 01.2012, p. 438-446.

Research output: Contribution to journalArticle

Noble, Christian G. ; Seh, Cheah Chen ; Chao, Alexander T. ; Shi, Pei-Yong. / Ligand-bound structures of the dengue virus protease reveal the active conformation. In: Journal of Virology. 2012 ; Vol. 86, No. 1. pp. 438-446.
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