疏水相互作用主导了对KRAS G12V新抗原的识别。
Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen.
发表日期：2023 Aug 21
作者：
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-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
来源：
Protein & Cell
摘要：
对于目前癌症治疗策略来说，特异性仍然是一个主要的挑战。突变相关新抗原（MANA）是遗传改变的产物，使它们成为高度特异性的治疗靶点。MANA是来自细胞内突变蛋白的HLA-presented（pHLA）肽段，而这些肽段对抗体类药物是无法访问的。在这里，我们描述了一个抗体-MANA pHLA复合物的低温电镜结构。具体地，我们确定了一个TCR模拟抗体结合到其MANA靶点——KRASG12V肽段，该肽段由HLA-A*03:01呈现。疏水残基似乎解释了突变的G12V残基的特异性。我们还通过X射线晶体学确定了野生型G12肽段与HLA-A*03:01结合的结构。基于这些结构，我们进行了筛选验证肽段特异性所需的关键残基。这些实验引导我们建立了一个通过疏水作用以外的方式，来区分HLA-A*03:01上突变和野生型肽段的模型。© 2023. Springer Nature Limited.
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.© 2023. Springer Nature Limited.