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Elucidation of New Binding Interactions with the Human Tsg101 Protein Using Modified HIV-1 Gag-p6 Derived Peptide Ligands

  1. Author:
    Kim, S. E.
    Liu, F.
    Im, Y. J.
    Stephen, A. G.
    Fivash, M. J.
    Waheed, A. A.
    Freed, E. O.
    Fisher, R. J.
    Hurley, J. H.
    Burke, T. R.

  2. Author Address

    [Kim, SE; Liu, F; Burke, TR] NCI Frederick, Biol Chem Lab, Discovery Program, CCR, Frederick, MD 21702 USA [Im, YJ; Hurley, JH] Natl Inst Diabet & Digest & Kidney, Mol Biol Lab, Frederick, MD 21702 USA [Stephen, AG; Fisher, RJ] NCI Frederick, Prot Chem Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA [Fivash, MJ] NCI Frederick, Data Management Syst Inc, Frederick, MD 21702 USA [Waheed, AA; Freed, EO] NCI Frederick, HIV Drug Resistance Program, CCR, Frederick, MD 21702 USA;Burke, TR (reprint author), NCI Frederick, Biol Chem Lab, Discovery Program, CCR, Frederick, MD 21702 USA;tburke@helix.nih.gov
    1. Year: 2011
    2. Date: May
  2. Journal: Acs Medicinal Chemistry Letters
    1. 2
    2. 5
    3. Pages: 337-341
  4. Type of Article: Article
  5. ISSN: 1948-5875
  1. Abstract:

    Targeting protein protein interactions is gaining greater recognition as an attractive approach to therapeutic development. An example of this may be found with the human cellular protein encoded by the tumor susceptibility gene 101 (Tsg101), where interaction with the p6 C-terminal domain of the nascent viral Gag protein is required for HIV-1 particle budding and release. This association of Gag with Tsg101 is highly dependent on a "Pro-Thr-Ala-Pro" ("PTAP") peptide sequence within the p6 protein. Although p6-derived peptides offer potential starting points for developing Tsg101-binding inhibitors, the affinities of canonical peptides are outside the useful range (K(d) values greater than 50 mu M). Reported herein are crystal structures of Tsg101 in complex with two structurally modified PTAP-derived peptides. These data define new regions of ligand interaction not previously identified with canonical peptide sequences. This information could be highly useful in the design of Tsg101-binding antagonists.

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External Sources

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  2. DOI: 10.1021/ml1002579
  3. View record in Web of Science®
  4. WOS: 000290691400003

Library Notes

  1. Fiscal Year: FY2010-2011
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