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Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen

Author

Listed:
  • Katharine M. Wright

    (The Johns Hopkins School of Medicine
    Howard Hughes Medical Institute
    Sidney Kimmel Comprehensive Cancer Center
    Merck & Co, Inc)

  • Sarah R. DiNapoli

    (Howard Hughes Medical Institute
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Michelle S. Miller

    (The Johns Hopkins School of Medicine
    Howard Hughes Medical Institute
    Sidney Kimmel Comprehensive Cancer Center
    Walter and Eliza Hall Institute)

  • P. Aitana Azurmendi

    (The Johns Hopkins School of Medicine
    Howard Hughes Medical Institute
    Sidney Kimmel Comprehensive Cancer Center)

  • Xiaowei Zhao

    (HHMI,19700 Helix Drive)

  • Zhiheng Yu

    (HHMI,19700 Helix Drive)

  • Mayukh Chakrabarti

    (The Johns Hopkins School of Medicine)

  • WuXian Shi

    (Brookhaven National Laboratory
    Case Western Reserve University)

  • Jacqueline Douglass

    (Howard Hughes Medical Institute
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Michael S. Hwang

    (Howard Hughes Medical Institute
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Emily Han-Chung Hsiue

    (Howard Hughes Medical Institute
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Novartis Institutes for BioMedical Research)

  • Brian J. Mog

    (Howard Hughes Medical Institute
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University)

  • Alexander H. Pearlman

    (Howard Hughes Medical Institute
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Suman Paul

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Maximilian F. Konig

    (Howard Hughes Medical Institute
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Drew M. Pardoll

    (Sidney Kimmel Comprehensive Cancer Center
    Johns Hopkins University School of Medicine)

  • Chetan Bettegowda

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Nickolas Papadopoulos

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Kenneth W. Kinzler

    (Sidney Kimmel Comprehensive Cancer Center
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Bert Vogelstein

    (Howard Hughes Medical Institute
    Sidney Kimmel Comprehensive Cancer Center
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Shibin Zhou

    (Sidney Kimmel Comprehensive Cancer Center
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Sandra B. Gabelli

    (The Johns Hopkins School of Medicine
    Sidney Kimmel Comprehensive Cancer Center
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

Abstract

Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific therapeutic targets. MANAs are HLA-presented (pHLA) peptides derived from intracellular mutant proteins that are otherwise inaccessible to antibody-based therapeutics. Here, we describe the cryo-EM structure of an antibody-MANA pHLA complex. Specifically, we determine a TCR mimic (TCRm) antibody bound to its MANA target, the KRASG12V peptide presented by HLA-A*03:01. Hydrophobic residues appear to account for the specificity of the mutant G12V residue. We also determine the structure of the wild-type G12 peptide bound to HLA-A*03:01, using X-ray crystallography. Based on these structures, we perform screens to validate the key residues required for peptide specificity. These experiments led us to a model for discrimination between the mutant and the wild-type peptides presented on HLA-A*03:01 based exclusively on hydrophobic interactions.

Suggested Citation

  • Katharine M. Wright & Sarah R. DiNapoli & Michelle S. Miller & P. Aitana Azurmendi & Xiaowei Zhao & Zhiheng Yu & Mayukh Chakrabarti & WuXian Shi & Jacqueline Douglass & Michael S. Hwang & Emily Han-Ch, 2023. "Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40821-w
    DOI: 10.1038/s41467-023-40821-w
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    References listed on IDEAS

    as
    1. Daichao Wu & D. Travis Gallagher & Ragul Gowthaman & Brian G. Pierce & Roy A. Mariuzza, 2020. "Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. Jude Canon & Karen Rex & Anne Y. Saiki & Christopher Mohr & Keegan Cooke & Dhanashri Bagal & Kevin Gaida & Tyler Holt & Charles G. Knutson & Neelima Koppada & Brian A. Lanman & Jonathan Werner & Aaron, 2019. "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity," Nature, Nature, vol. 575(7781), pages 217-223, November.
    3. Michael S. Hwang & Michelle S. Miller & Puchong Thirawatananond & Jacqueline Douglass & Katharine M. Wright & Emily Han-Chung Hsiue & Brian J. Mog & Tihitina Y. Aytenfisu & Michael B. Murphy & P. Aita, 2021. "Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. Jonathan M. Ostrem & Ulf Peters & Martin L. Sos & James A. Wells & Kevan M. Shokat, 2013. "K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions," Nature, Nature, vol. 503(7477), pages 548-551, November.
    5. Adham S. Bear & Tatiana Blanchard & Joseph Cesare & Michael J. Ford & Lee P. Richman & Chong Xu & Miren L. Baroja & Sarah McCuaig & Christina Costeas & Khatuna Gabunia & John Scholler & Avery D. Posey, 2021. "Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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    Cited by:

    1. Andrew C. McShan & David Flores-Solis & Yi Sun & Samuel E. Garfinkle & Jugmohit S. Toor & Michael C. Young & Nikolaos G. Sgourakis, 2023. "Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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