Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition
Recommended Citation
McShan A, Flores-Solis D, Sun Y, Garfinkle S, Toor JS, Young M, Sgourakis N. Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition. Nat Commun 2023; 14(1):8204-8204.
Document Type
Article
Publication Date
12-11-2023
Publication Title
Nat Commun
Keywords
Humans, Antigens, Neoplasm, Neoplasms, Peptides, Histocompatibility Antigens, HLA-A Antigens
Abstract
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 RAS(55-64) 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 NRAS(Q61K)/HLA-A*01:01, which enables modeling of other common RAS(55-64) 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 NRAS(Q61K) 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.
Medical Subject Headings
Humans; Antigens, Neoplasm; Neoplasms; Peptides; Histocompatibility Antigens; HLA-A Antigens
PubMed ID
38081856
Volume
14
Issue
1
First Page
8204
Last Page
8204
