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Diverse HIV viruses are targeted by a conformationally dynamic antiviral

Nature Structural & Molecular Biology volume 19, pages 411416 (2012) | Download Citation


Rhesus macaque TRIMCyp (RhTC) is a potent primate antiviral host protein that inhibits the replication of diverse HIV viruses. Here we show that it has acquired the ability to target multiple viruses by evolving an active site that interconverts between multiple conformations. Mutations that have relieved active site constraints allow RhTC to dynamically sample conformational space, including radically different conformers that target both HIV-1 and HIV-2 viruses. Introduction of a reversible constraint into RhTC allows specificity to be switched between a single conformation specific for HIV-1 and a dynamic ensemble that targets multiple viruses. These results show that conformational diversity can be used to expand the target diversity of innate immune receptors by supplementing their limited genetic variability with variability in protein structure.

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We thank the staff at Beamline ID23-1 of the ESRF (Grenoble, France) and Beamline I03 of the Diamond Light Source (Didcot, UK) for expert assistance and D. Neuhaus and P. Evans for helpful discussions. O. Perisic (MRC Laboratory of Molecular Biology) for plasmids. This work was funded by the Medical Research Council (UK) and the European Research Council (281627-IAI).

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Author notes

    • Matthew E C Caines
    •  & Katsiaryna Bichel

    These authors contributed equally to this work.


  1. Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Cambridge, UK.

    • Matthew E C Caines
    • , Katsiaryna Bichel
    • , Amanda J Price
    • , William A McEwan
    • , Stefan M V Freund
    •  & Leo C James
  2. Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London, UK.

    • Greg J Towers
  3. Retrovirus Research Laboratory, Medical Research Council-University of Glasgow Centre for Virus Research, University of Glasgow, UK.

    • Brian J Willett


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M.E.C.C. and A.J.P. determined crystal structures and carried out ITC experiments; K.B. did NMR dynamics studies; S.M.V.F. did NMR dynamics studies and co-wrote the manuscript; W.A.M. carried out ITC experiments; G.J.T. and B.J.W. supplied materials and assisted with writing; L.C.J. designed experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Stefan M V Freund or Leo C James.

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