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Issue 32, 2019
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Targeting trimeric transmembrane domain 5 of oncogenic latent membrane protein 1 using a computationally designed peptide

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Abstract

Protein–protein interactions are involved in diverse biological processes. These interactions are therefore vital targets for drug development. However, the design of peptide modulators targeting membrane-based protein–protein interactions is a challenging goal owing to the lack of experimentally-determined structures and efficient protocols to probe their functions. Here we employed rational peptide design and molecular dynamics simulations to design a membrane-insertable peptide that disrupts the strong trimeric self-association of the fifth transmembrane domain (TMD5) of the oncogenic Epstein–Barr virus (EBV) latent membrane protein-1 (LMP-1). The designed anti-TMD5 peptide formed 1 : 2 heterotrimers with TMD5 in micelles and inhibited TMD5 oligomerization in bacterial membranes. Moreover, the designed peptide inhibited LMP-1 homotrimerization based on NF-κB activity in EVB positive lymphoma cells. The results indicated that the designed anti-TMD5 peptide may represent a promising starting point for elaboration of anti-EBV therapeutics via inhibition of LMP-1 oligomerization. To the best of our knowledge, this represents the first example of disrupting homotrimeric transmembrane helices using a designed peptide inhibitor.

Graphical abstract: Targeting trimeric transmembrane domain 5 of oncogenic latent membrane protein 1 using a computationally designed peptide

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Publication details

The article was received on 21 May 2019, accepted on 26 Jun 2019 and first published on 27 Jun 2019


Article type: Edge Article
DOI: 10.1039/C9SC02474C
Chem. Sci., 2019,10, 7584-7590
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Targeting trimeric transmembrane domain 5 of oncogenic latent membrane protein 1 using a computationally designed peptide

    Y. Wang, Y. Peng, B. Zhang, X. Zhang, H. Li, A. J. Wilson, K. S. Mineev and X. Wang, Chem. Sci., 2019, 10, 7584
    DOI: 10.1039/C9SC02474C

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