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Crystal structure of the conserved herpesvirus fusion regulator complex gH–gL

Nature Structural & Molecular Biology volume 17, pages 882888 (2010) | Download Citation

Abstract

Herpesviruses, which cause many incurable diseases, infect cells by fusing viral and cellular membranes. Whereas most other enveloped viruses use a single viral catalyst called a fusogen, herpesviruses, inexplicably, require two conserved fusion-machinery components, gB and the heterodimer gH–gL, plus other nonconserved components. gB is a class III viral fusogen, but unlike other members of its class, it does not function alone. We determined the crystal structure of the gH ectodomain bound to gL from herpes simplex virus 2. gH–gL is an unusually tight complex with a unique architecture that, unexpectedly, does not resemble any known viral fusogen. Instead, we propose that gH–gL activates gB for fusion, possibly through direct binding. Formation of a gB–gH–gL complex is critical for fusion and is inhibited by a neutralizing antibody, making the gB–gH–gL interface a promising antiviral target.

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Acknowledgements

We thank L. Friedman for making the gHΔ48–gL baculovirus expression construct, M. Shaner for preliminary characterization of the gL(161t) mutant, D. King for MS, A. Héroux for collecting X-ray diffraction data on SeMet-derivative crystals, H. Lou, C. Whitbeck and M. Ponce de Leon for their earlier contributions to this project and S.C. Harrison for helpful discussions and critical reading of the manuscript. This work was funded by the US National Institutes of Health (NIH) grant 1DP20D001996 and by the Pew Scholar Program in Biomedical Sciences (E.E.H.) as well as by the NIH grants AI18289 (G.H.C.), AI056045 (R.J.E.) and AI076231 (R.J.E.). This work is based on research conducted at the Advanced Photon Source on the Northeastern Collaborative Access Team beamlines, which are supported by award RR-15301 from the National Center for Researcher Resources at NIH. Use of the Advanced Photon Source is supported by the US Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. Use of the National Synchrotron Light Source, Brookhaven National Laboratory, is supported by the US Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886.

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Affiliations

  1. Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA.

    • Tirumala K Chowdary
    •  & Ekaterina E Heldwein
  2. Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Tina M Cairns
    • , Doina Atanasiu
    •  & Gary H Cohen
  3. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Roselyn J Eisenberg

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Contributions

T.K.C., T.M.C. and D.A. performed the experimental work; T.K.C. and E.E.H. performed computational analysis of data; T.K.C., T.M.C., D.A., G.H.C., R.J.E. and E.E.H. interpreted the results and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ekaterina E Heldwein.

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https://doi.org/10.1038/nsmb.1837

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