Solution structure of a hydrocarbon stapled peptide inhibitor in complex with monomeric C-terminal domain of HIV-1 capsid

Shibani Bhattacharya, Hongtao Zhang, Asim K. Debnath, David Cowburn

Research output: Contribution to journalArticle

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Abstract

The human immunodeficiency virus type 1 (HIV-1) capsid protein plays a critical role in virus core particle assembly and is an important target for novel therapeutic strategies. In a previous study, we characterized the binding affinity of a hydrocarbon stapled helical peptide, NYAD-1, for the capsid protein (Kd - 1 μM) and demonstrated its ability to penetrate the cell membrane (Zhang, H., Zhao, Q., Bhattacharya, S., Waheed, A. A., Tong, X., Hong, A., Heck, S., Goger, M., Cowburn, D., Freed, E. O., and Debnath, A. K. (2008) J. Mol. Biol. 378, 565-580). In cell-based assays, NYAD-1 colocalized with the Gag polyprotein during traffic to the plasma membrane and disrupted the formation of mature and immature virus particles in vitro systems. Here, we complement the cellular and biochemical data with structural characterization of the interactions between the capsid and a soluble peptide analogue, NYAD-13. Solution NMR methods were used to determine a high resolution structure of the complex between the inhibitor and a monomeric form of the C-terminal domain of the capsid protein (mCA-CTD). The intermolecular interactions are mediated by the packing of hydrophobic side chains at the buried interface and unperturbed by the presence of the olefinic chain on the solvent-exposed surface of the peptide. The results of the structural analysis provide valuable insight into the determinants for high affinity and selective inhibitors for HIV-1 particle assembly.

Original languageEnglish (US)
Pages (from-to)16274-16278
Number of pages5
JournalJournal of Biological Chemistry
Volume283
Issue number24
DOIs
StatePublished - Jun 13 2008

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Capsid
Capsid Proteins
Hydrocarbons
Viruses
Virion
HIV-1
Peptides
Cell membranes
Cell Membrane
gag Gene Products
Structural analysis
Assays
Nuclear magnetic resonance
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Solution structure of a hydrocarbon stapled peptide inhibitor in complex with monomeric C-terminal domain of HIV-1 capsid. / Bhattacharya, Shibani; Zhang, Hongtao; Debnath, Asim K.; Cowburn, David.

In: Journal of Biological Chemistry, Vol. 283, No. 24, 13.06.2008, p. 16274-16278.

Research output: Contribution to journalArticle

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