Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen

Wright, KM; DiNapoli, SR; Miller, MS; Aitana Azurmendi, P; Zhao, X; Yu, Z; Chakrabarti, M; Shi, W; Douglass, J; Hwang, MS; Hsiue, EH; Mog, BJ; Pearlman, AH; Paul, S; Konig, MF; Pardoll, DM; Bettegowda, C; Papadopoulos, N; Kinzler, KW; Vogelstein, B; Zhou, S; Gabelli, SB

Author(s): Wright, KM; DiNapoli, SR; Miller, MS; Aitana Azurmendi, P; Zhao, X; Yu, Z; Chakrabarti, M; Shi, W; Douglass, J; Hwang, MS; Hsiue, EH; Mog, BJ; Pearlman, AH; Paul, S; Konig, MF; Pardoll, DM; Bettegowda, C; Papadopoulos, N; Kinzler, KW; Vogelstein, B; Zhou, S; Gabelli, SB;
Details: Publication Year 2023-08-21,Volume 14,Issue #1,Page 5063
Journal Title: Nature Communications
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.
Publisher: NPG
Keywords: *Proto-Oncogene Proteins p21(ras)/genetics; *Antibodies; Recognition, Psychology; Hydrophobic and Hydrophilic Interactions; HLA-A Antigens/genetics
Research Division(s): Structural Biology
PubMed ID: 37604828
Publisher's Version: https://doi.org/10.1038/s41467-023-40821-w
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-023-40821-w.
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41467-023-40821-w.pdf - (4.01MB, application/pdf)

Creation Date: 2023-08-28 09:37:22

Last Modified: 2023-08-28 09:56:29