Towards the Design of Flavivirus Helicase/NTPase Inhibitors: Crystallographic and Mutagenesis Studies of the Dengue Virus NS3 Helicase Catalytic Domain

  1. Gregory Bock Organizer and
  2. Jamie Goode
  1. Ting Xu1,†,
  2. Aruna Sampath2,‡,
  3. Alex Chao2,
  4. Daying Wen2,
  5. Max Nanao3,
  6. Dahai Luo1,
  7. Patrick Chene4,
  8. Subhash G. Vasudevan5 and
  9. Julien Lescar1,§

Published Online: 7 OCT 2008

DOI: 10.1002/0470058005.ch7

New Treatment Strategies for Dengue and Other Flaviviral Diseases: Novartis Foundation Symposium 277

New Treatment Strategies for Dengue and Other Flaviviral Diseases: Novartis Foundation Symposium 277

How to Cite

Xu, T., Sampath, A., Chao, A., Wen, D., Nanao, M., Luo, D., Chene, P., Vasudevan, S. G. and Lescar, J. (2008) Towards the Design of Flavivirus Helicase/NTPase Inhibitors: Crystallographic and Mutagenesis Studies of the Dengue Virus NS3 Helicase Catalytic Domain, in New Treatment Strategies for Dengue and Other Flaviviral Diseases: Novartis Foundation Symposium 277 (eds G. Bock and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/0470058005.ch7

Author Information

  1. 1

    School of Biological Sciences, Nanyang Technological University, 60, Nanyang Drive Singapore 637551

  2. 2

    Novartis Institute for Tropical Diseases, 10 Biopolis Road, Chromos Building, Singapore 138670

  3. 3

    EMBL, Grenoble Outstation, Grenoble, 38000, France

  4. 4

    Novartis Institute for Biomedical Research, Oncology Department, CH-4002 Basel, Switzerland

  5. 5

    Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670

  1. These two authors have contributed equally to this work.

  2. These two authors have contributed equally to this work.

  3. §

    This paper was presented at the symposium by Julien Lescar, to whom correspondence should be addressed.

Publication History

  1. Published Online: 7 OCT 2008
  2. Published Print: 25 AUG 2006

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470016435

Online ISBN: 9780470058008

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Keywords:

  • Flavivirus;
  • Dengue virus;
  • yellow fever virus;
  • RNA helicase;
  • ATPase;
  • dynamics. Inhibitor design

Summary

Infectious diseases caused by flaviviruses are important emerging public health concerns and new vaccines and therapeutics are urgently needed. The NS3 protein from flavivirus is a multifunctional protein with protease, helicase and nucleoside 5′ triphosphatase activities (NTPase). Thus, NS3 plays a crucial role in viral replication and represents an interesting target for the development of specific antiviral inhibitors. We have solved the structure of an enzymatically active fragment of the dengue virus NTPase/ helicase C-terminal catalytic domain in several related crystal forms. The structure is composed of three domains, bears an asymmetric distribution of charges and comprises a tunnel large enough to accommodate single strand RNA. A concave face formed by domains 2 and 3 is proposed to bind a nucleic acid duplex substrate. Comparison of the various copies of dengue and yellow fever virus NS3 NTPase/helicase catalytic domains reveals mobile regions of the enzyme. Such dynamic behaviour is likely to be coupled with directional translocation along the single strand nucleic acid substrate during strand separation. We used structure-based site directed mutagenesis to identify regions of the enzyme that are crucial for its ATPase or nucleic acid duplex unwinding activity.