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Structure of the Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein

Nature Structural Biology volume 9, pages 812–817 (2002)Cite this article

Abstract

The structural proteins of HIV and Ebola display PTAP peptide motifs (termed 'late domains') that recruit the human protein Tsg101 to facilitate virus budding. Here we present the solution structure of the UEV (ubiquitin E2 variant) binding domain of Tsg101 in complex with a PTAP peptide that spans the late domain of HIV-1 p6Gag. The UEV domain of Tsg101 resembles E2 ubiquitin-conjugating enzymes, and the PTAP peptide binds in a bifurcated groove above the vestigial enzyme active site. Each PTAP residue makes important contacts, and the Ala 9-Pro 10 dipeptide binds in a deep pocket of the UEV domain that resembles the X-Pro binding pockets of SH3 and WW domains. The structure reveals the molecular basis of HIV PTAP late domain function and represents an attractive starting point for the design of novel inhibitors of virus budding.

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Figure 1: Schematic representations of human Tsg101 (390 amino acids) and HIV-1 Gag (500 amino acids).
Figure 2: Determination of the Tsg101 UEV–PTAP peptide complex structure.
Figure 3: Molecular recognition in the Tsg101 UEV–PTAP peptide complex.
Figure 4: Proline recognition by Tsg101 UEV.

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Acknowledgements

We thank B. Schackmann and S. Endicott for peptide synthesis and purification, D. Edwards for technical NMR support and E. Ross for computer support. This work was supported by NIH funding to W.I.S. The Utah Biomolecular NMR Facility is supported by grants from the NIH and the NSF.

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Author notes

  1. Owen Pornillos, Steven L. Alam and Darrell R. Davis: These authors contributed equally to the structure determination.

Authors and Affiliations

  1. Department of Biochemistry, University of Utah, Salt Lake City, 84132, Utah, USA

    Owen Pornillos, Steven L. Alam, Darrell R. Davis & Wesley I. Sundquist

  2. Department of Medicinal Chemistry, University of Utah, Salt Lake City, 84132, Utah, USA

    Darrell R. Davis

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  1. Owen Pornillos
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  2. Steven L. Alam
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  4. Wesley I. Sundquist
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Correspondence to Darrell R. Davis or Wesley I. Sundquist.

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Pornillos, O., Alam, S., Davis, D. et al. Structure of the Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein. Nat Struct Mol Biol 9, 812–817 (2002). https://doi.org/10.1038/nsb856

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