<br>疏水相互作用主导 KRAS G12V 新抗原的识别,Nature Communications

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疏水相互作用主导 KRAS G12V 新抗原的识别
Nature Communications ( IF 14.7 ) Pub Date : 2023-08-21 , DOI: 10.1038/s41467-023-40821-w
Katharine M Wright _{1,

2,

3,

4} , Sarah R DiNapoli _{2,

5,

6} , Michelle S Miller _{1,

2,

3,

7} , P Aitana Azurmendi _{1,

2,

3} , Xiaowei Zhao ₈ , Zhiheng Yu ₈ , Mayukh Chakrabarti ₁ , WuXian Shi _{9,

10} , Jacqueline Douglass _{2,

5,

6} , Michael S Hwang _{2,

5,

6} , Emily Han-Chung Hsiue _{2,

5,

6,

11} , Brian J Mog _{2,

5,

6,

12} , Alexander H Pearlman _{2,

5,

6} , Suman Paul _{5,

6,

13,

14} , Maximilian F Konig _{2,

5,

6,

15} , Drew M Pardoll _{3,

13} , Chetan Bettegowda _{5,

6,

13,

16} , Nickolas Papadopoulos _{5,

6,

13,

17} , Kenneth W Kinzler _{3,

5,

6,

13} , Bert Vogelstein _{2,

3,

5,

6,

13,

17} , Shibin Zhou _{3,

5,

6,

13} , Sandra B Gabelli _{1,

3,

4,

13,

18}

Affiliation

Department of Biophysics and Biophysical Chemistry, The Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21287, USA.
Discovery Chemistry, Protein and Structural Chemistry, Merck & Co, Inc, West Point, PA, 19846, USA.
Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia.
Janelia Research Campus, HHMI,19700 Helix Drive, Ashburn, VA, 20147, USA.
Energy & Photon Sciences Directorate, Brookhaven National Laboratory, Upton, NY, 11973, USA.
Case Center for Synchrotron Biosciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
Novartis Institutes for BioMedical Research, 250 Massachusetts Ave, Cambridge, MA, 02139, USA.
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Division of Hematologic Malignancies and Bone Marrow Transplantation, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA.
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

特异性仍然是当前癌症治疗策略的主要挑战。突变相关新抗原（MANA）是基因改变的产物，使其成为高度特异性的治疗靶点。 MANA 是 HLA 呈递 (pHLA) 肽，源自细胞内突变蛋白，否则基于抗体的疗法无法获得这些突变蛋白。在这里，我们描述了抗体-MANA pHLA 复合物的冷冻电镜结构。具体来说，我们确定了与其 MANA 靶标（由 HLA-A*03:01 呈递的 KRAS ^G12V肽）结合的 TCR 模拟 (TCRm) 抗体。疏水性残基似乎解释了突变体 G12V 残基的特异性。我们还使用 X 射线晶体学确定了与 HLA-A*03:01 结合的野生型 G12 肽的结构。基于这些结构，我们进行筛选以验证肽特异性所需的关键残基。这些实验使我们建立了一个仅基于疏水相互作用来区分 HLA-A*03:01 上呈现的突变型和野生型肽的模型。

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更新日期：2023-08-21

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