The dengue virus NS2B-NS3 protease retains the closed conformation in the complex with BPTI

Wan Na Chen; Karin V. Loscha; Christoph Nitsche; Bim Graham; Gottfried Otting

doi:10.1016/j.febslet.2014.05.018

The dengue virus NS2B-NS3 protease retains the closed conformation in the complex with BPTI

Wan Na Chen, Karin V. Loscha, Christoph Nitsche, Bim Graham, Gottfried Otting^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

50 Citations (Scopus)

Abstract

The C-terminal β-hairpin of NS2B (NS2Bc) in the dengue virus NS2B-NS3 protease is required for full enzymatic activity. In crystal structures without inhibitor and in the complex with bovine pancreatic trypsin inhibitor (BPTI), NS2Bc is displaced from the active site. In contrast, nuclear magnetic resonance (NMR) studies in solution only ever showed NS2Bc in the enzymatically active closed conformation. Here we demonstrate by pseudocontact shifts from a lanthanide tag that NS2Bc remains in the closed conformation also in the complex with BPTI. Therefore, the closed conformation is the best template for drug discovery.

Original language	English
Pages (from-to)	2206-2211
Number of pages	6
Journal	FEBS Letters
Volume	588
Issue number	14
DOIs	https://doi.org/10.1016/j.febslet.2014.05.018
Publication status	Published - 27 Jun 2014

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10.1016/j.febslet.2014.05.018

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title = "The dengue virus NS2B-NS3 protease retains the closed conformation in the complex with BPTI",

abstract = "The C-terminal β-hairpin of NS2B (NS2Bc) in the dengue virus NS2B-NS3 protease is required for full enzymatic activity. In crystal structures without inhibitor and in the complex with bovine pancreatic trypsin inhibitor (BPTI), NS2Bc is displaced from the active site. In contrast, nuclear magnetic resonance (NMR) studies in solution only ever showed NS2Bc in the enzymatically active closed conformation. Here we demonstrate by pseudocontact shifts from a lanthanide tag that NS2Bc remains in the closed conformation also in the complex with BPTI. Therefore, the closed conformation is the best template for drug discovery.",

keywords = "Bovine pancreatic trypsin inhibitor, Dengue virus protease, Lanthanide tag, NMR spectroscopy, Pseudocontact shift",

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AU - Chen, Wan Na

AU - Loscha, Karin V.

AU - Nitsche, Christoph

AU - Graham, Bim

AU - Otting, Gottfried

PY - 2014/6/27

Y1 - 2014/6/27

N2 - The C-terminal β-hairpin of NS2B (NS2Bc) in the dengue virus NS2B-NS3 protease is required for full enzymatic activity. In crystal structures without inhibitor and in the complex with bovine pancreatic trypsin inhibitor (BPTI), NS2Bc is displaced from the active site. In contrast, nuclear magnetic resonance (NMR) studies in solution only ever showed NS2Bc in the enzymatically active closed conformation. Here we demonstrate by pseudocontact shifts from a lanthanide tag that NS2Bc remains in the closed conformation also in the complex with BPTI. Therefore, the closed conformation is the best template for drug discovery.

AB - The C-terminal β-hairpin of NS2B (NS2Bc) in the dengue virus NS2B-NS3 protease is required for full enzymatic activity. In crystal structures without inhibitor and in the complex with bovine pancreatic trypsin inhibitor (BPTI), NS2Bc is displaced from the active site. In contrast, nuclear magnetic resonance (NMR) studies in solution only ever showed NS2Bc in the enzymatically active closed conformation. Here we demonstrate by pseudocontact shifts from a lanthanide tag that NS2Bc remains in the closed conformation also in the complex with BPTI. Therefore, the closed conformation is the best template for drug discovery.

KW - Bovine pancreatic trypsin inhibitor

KW - Dengue virus protease

KW - Lanthanide tag

KW - NMR spectroscopy

KW - Pseudocontact shift

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DO - 10.1016/j.febslet.2014.05.018

M3 - Article

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VL - 588

SP - 2206

EP - 2211

JO - FEBS Letters

JF - FEBS Letters

IS - 14

ER -

The dengue virus NS2B-NS3 protease retains the closed conformation in the complex with BPTI

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