7STF

Structure of KRAS G12V/HLA-A*03:01 in complex with antibody fragment V2

7STF の概要

• エントリーDOI: 10.2210/pdb7stf/pdb
• EMDBエントリー: 25427
• 分子名称: IgG, Fab Heavy Chain V2, KRAS G12V (7-16), IgG, Fab Light Chain V2, ... (5 entities in total)
• 機能のキーワード: complex, mhc-i, kras, hla-a3, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 92139.32

構造登録者

Wright, K.M.,Gabelli, S.B.,Miller, M. (登録日: 2021-11-12, 公開日: 2023-05-31, 最終更新日: 2024-11-20)

主引用文献

Wright, K.M.,DiNapoli, S.R.,Miller, M.S.,Aitana Azurmendi, P.,Zhao, X.,Yu, Z.,Chakrabarti, M.,Shi, W.,Douglass, J.,Hwang, M.S.,Hsiue, E.H.,Mog, B.J.,Pearlman, A.H.,Paul, S.,Konig, M.F.,Pardoll, D.M.,Bettegowda, C.,Papadopoulos, N.,Kinzler, K.W.,Vogelstein, B.,Zhou, S.,Gabelli, S.B.
Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen.
Nat Commun, 14:5063-5063, 2023

PubMed 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 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.

PubMed: 37604828
DOI: 10.1038/s41467-023-40821-w

実験手法

ELECTRON MICROSCOPY (3.14 Å)