Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition.
Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition.
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DOI：
10.1038/s41467-023-43654-9
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发表时间：
2023-12-11
影响因子：
16.6
通讯作者：
Sgourakis, Nikolaos G.
中科院分区：
文献类型：
--
作者：
McShan, Andrew C.;Flores-Solis, David;Sun, Yi;Garfinkle, Samuel E.;Toor, Jugmohit S.;Young, Michael C.;Sgourakis, Nikolaos G.
围绕肿瘤新抗原的多肽/人类白细胞抗原(Phla)蛋白复合体的构象景观为向自体T细胞、疫苗和基于抗体的治疗方式选择靶点提供了理论基础。在这里，我们使用互补的生物物理和计算方法，表征了由常见的人类白细胞抗原-A*01：01同种异型呈现的反复出现的RAS55-Q61新表位。我们将稀疏核磁共振限制条件与Rosetta对接相结合来确定NRASQ61K/HLAA*01：01的溶液结构，这使得对其他常见的RAS55-新表位的建模成为可能。氢/氢交换质谱仪实验与分子动力学模拟相结合，揭示了一组与免疫受体识别相关的常见Q61新表位在溶剂可及性和构象可塑性方面的差异。最后，我们预测了NRASQ61K抗原的结合，并提供了跨越整个HLA等位基因图谱的结构模型，以及对HLA-A*01：191、HL A-B*15：01和HL A-C*08：02的体外验证。我们的工作为描述临床相关的肿瘤治疗新表位/人类白细胞抗原靶标的溶液表面特征和免疫原性提供了基础。作者使用综合结构生物学方法来阐明公共肿瘤抗原RASQ61家族的分子特征。这些信息可以用来开发靶向疗法来对抗一系列癌症。
The conformational landscapes of peptide/human leucocyte antigen (pHLA) protein complexes encompassing tumor neoantigens provide a rationale for target selection towards autologous T cell, vaccine, and antibody-based therapeutic modalities. Here, using complementary biophysical and computational methods, we characterize recurrent RAS55-64 Q61 neoepitopes presented by the common HLA-A*01:01 allotype. We integrate sparse NMR restraints with Rosetta docking to determine the solution structure of NRASQ61K/HLA-A*01:01, which enables modeling of other common RAS55-64 neoepitopes. Hydrogen/deuterium exchange mass spectrometry experiments alongside molecular dynamics simulations reveal differences in solvent accessibility and conformational plasticity across a panel of common Q61 neoepitopes that are relevant for recognition by immunoreceptors. Finally, we predict binding and provide structural models of NRASQ61K antigens spanning the entire HLA allelic landscape, together with in vitro validation for HLA-A*01:191, HLA-B*15:01, and HLA-C*08:02. Our work provides a basis to delineate the solution surface features and immunogenicity of clinically relevant neoepitope/HLA targets for cancer therapy. The authors use an integrative structural biology approach to elucidate molecular features of the RAS Q61 family of public tumor antigens. This information can be used to develop targeted therapeutics to combat a range of cancers.
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影响因子：
16.6
作者：
Gupta, Sagar;Nerli, Santrupti;Kandy, Sreeja Kutti;Mersky, Glenn L.;Sgourakis, Nikolaos G.
通讯作者：
Sgourakis, Nikolaos G.
影响因子：
16.6
作者：
Ebrahimi-Nik H;Moussa M;Englander RP;Singhaviranon S;Michaux J;Pak H;Miyadera H;Corwin WL;Keller GLJ;Hagymasi AT;Shcheglova TV;Coukos G;Baker BM;Mandoiu II;Bassani-Sternberg M;Srivastava PK
通讯作者：
Srivastava PK
影响因子：
4.8
作者：
Hawse, William F.;Gloor, Brian E.;Baker, Brian M.
通讯作者：
Baker, Brian M.
DOI：
10.1073/pnas.1201586109
发表时间：
2012-03-20
影响因子：
11.1
作者：
Eisen, Herman N.;Hou, Xun Helen;Cohen, Richard J.
通讯作者：
Cohen, Richard J.
影响因子：
4.8
作者：
Hassan, Chopie;Chabrol, Eric;van Veelen, Peter A.
通讯作者：
van Veelen, Peter A.