Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen

Katharine M. Wright; Sarah R. DiNapoli; Michelle S. Miller; P. Aitana Azurmendi; Xiaowei Zhao; Zhiheng Yu; Mayukh Chakrabarti; Wu Xian Shi; Jacqueline Douglass; Michael S. Hwang; Emily Han Chung Hsiue; Brian J. Mog; Alexander H. Pearlman; Suman Paul; Maximilian F. Konig; Drew M. Pardoll; Chetan Bettegowda; Nickolas Papadopoulos; Kenneth W. Kinzler; Bert Vogelstein; Shibin Zhou; Sandra B. Gabelli

doi:10.1038/s41467-023-40821-w

Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen

Katharine M. Wright, Sarah R. DiNapoli, Michelle S. Miller, P. Aitana Azurmendi, Xiaowei Zhao, Zhiheng Yu, Mayukh Chakrabarti, Wu Xian Shi, Jacqueline Douglass, Michael S. Hwang, Emily Han Chung Hsiue, Brian J. Mog, Alexander H. Pearlman, Suman Paul, Maximilian F. Konig, Drew M. Pardoll, Chetan Bettegowda, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert VogelsteinShibin Zhou, Sandra B. Gabelli

Research output: Contribution to journal › Article › peer-review

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 KRAS^G12V 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.

Original language	English (US)
Article number	5063
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-40821-w
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-023-40821-w

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Wright, K. M., DiNapoli, S. R., Miller, M. S., Aitana Azurmendi, P., Zhao, X., Yu, Z., Chakrabarti, M., Shi, W. X., Douglass, J., Hwang, M. S., Hsiue, E. H. C., Mog, B. J., Pearlman, A. H., Paul, S., Konig, M. F., Pardoll, D. M., Bettegowda, C., Papadopoulos, N., Kinzler, K. W., ... Gabelli, S. B. (2023). Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen. Nature communications, 14(1), Article 5063. https://doi.org/10.1038/s41467-023-40821-w

Wright, KM, DiNapoli, SR, Miller, MS, Aitana Azurmendi, P, Zhao, X, Yu, Z, Chakrabarti, M, Shi, WX, Douglass, J, Hwang, MS, Hsiue, EHC, Mog, BJ, Pearlman, AH, Paul, S , Konig, MF , Pardoll, DM , Bettegowda, C , Papadopoulos, N , Kinzler, KW , Vogelstein, B , Zhou, S & Gabelli, SB 2023, 'Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen', Nature communications, vol. 14, no. 1, 5063. https://doi.org/10.1038/s41467-023-40821-w

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title = "Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen",

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.",

author = "Wright, {Katharine M.} and DiNapoli, {Sarah R.} and Miller, {Michelle S.} and {Aitana Azurmendi}, P. and Xiaowei Zhao and Zhiheng Yu and Mayukh Chakrabarti and Shi, {Wu Xian} and Jacqueline Douglass and Hwang, {Michael S.} and Hsiue, {Emily Han Chung} and Mog, {Brian J.} and Pearlman, {Alexander H.} and Suman Paul and Konig, {Maximilian F.} and Pardoll, {Drew M.} and Chetan Bettegowda and Nickolas Papadopoulos and Kinzler, {Kenneth W.} and Bert Vogelstein and Shibin Zhou and Gabelli, {Sandra B.}",

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AU - Wright, Katharine M.

AU - DiNapoli, Sarah R.

AU - Miller, Michelle S.

AU - Aitana Azurmendi, P.

AU - Zhao, Xiaowei

AU - Yu, Zhiheng

AU - Chakrabarti, Mayukh

AU - Shi, Wu Xian

AU - Douglass, Jacqueline

AU - Hwang, Michael S.

AU - Hsiue, Emily Han Chung

AU - Mog, Brian J.

AU - Pearlman, Alexander H.

AU - Paul, Suman

AU - Konig, Maximilian F.

AU - Pardoll, Drew M.

AU - Bettegowda, Chetan

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth W.

AU - Vogelstein, Bert

AU - Zhou, Shibin

AU - Gabelli, Sandra B.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen

Abstract

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