@article {68957,
	title = {Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen.},
	journal = {Nature Communications},
	volume = {14},
	year = {2023},
	month = {2023 Aug 21},
	pages = {5063},
	abstract = {<p>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 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.</p>
},
	keywords = {Antibodies, HLA-A Antigens, Hydrophobic and Hydrophilic Interactions, Proto-Oncogene Proteins p21(ras), Recognition, Psychology},
	issn = {2041-1723},
	doi = {10.1038/s41467-023-40821-w},
	author = {Wright, Katharine M and DiNapoli, Sarah R and Miller, Michelle S and Aitana Azurmendi, P and Zhao, Xiaowei and Yu, Zhiheng and Chakrabarti, Mayukh and Shi, WuXian and Douglass, Jacqueline and Hwang, Michael S and Hsiue, Emily Han-Chung and Mog, Brian J and Pearlman, Alexander H and Paul, Suman and Konig, Maximilian F and Pardoll, Drew M and Bettegowda, Chetan and Papadopoulos, Nickolas and Kinzler, Kenneth W and Vogelstein, Bert and Zhou, Shibin and Gabelli, Sandra B}
}
