8RO5

HLA-A3 restricted mG12V-TCR

Summary for 8RO5

• Entry DOI: 10.2210/pdb8ro5/pdb
• Related: 8RNI 8VJZ
• Descriptor: Chains: B, Chains: A (3 entities in total)
• Functional Keywords: hla-a*03:01 with kras-g12v-10mer, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 50453.46

Authors

Sim, M.J.W.,Sun, P.D. (deposition date: 2024-01-11, release date: 2025-01-22)

Primary citation

Sim, M.J.W.,Hanada, K.I.,Stotz, Z.,Yu, Z.,Lu, J.,Brennan, P.,Quastel, M.,Gillespie, G.M.,Long, E.O.,Yang, J.C.,Sun, P.D.
Identification and structural characterization of a mutant KRAS-G12V specific TCR restricted by HLA-A3.
Eur.J.Immunol., 54:e2451079-e2451079, 2024

PubMed Abstract: Mutations in KRAS are some of the most common across multiple cancer types and are thus attractive targets for therapy. Recent studies demonstrated that mutant KRAS generates immunogenic neoantigens that are targetable by adoptive T-cell therapy in metastatic diseases. To expand mutant KRAS-specific immunotherapies, it is critical to identify additional HLA-I allotypes that can present KRAS neoantigens and their cognate T-cell receptors (TCR). Here, we identified a murine TCR specific to a KRAS-G12V neoantigen (VVVGAVGVGK) using a vaccination approach with transgenic mice expressing HLA-A*03:01 (HLA-A3). This TCR demonstrated exquisite specificity for mutant G12V and not WT KRAS peptides. To investigate the molecular basis for neoantigen recognition by this TCR, we determined its structure in complex with HLA-A3(G12V). G12V-TCR CDR3β and CDR1β formed a hydrophobic pocket to interact with p6 Val of the G12V but not the WT KRAS peptide. To improve the tumor sensitivity of this TCR, we designed rational substitutions to improve TCR:HLA-A3 contacts. Two substitutions exhibited modest improvements in TCR binding avidity to HLA-A3 (G12V) but did not sufficiently improve T-cell sensitivity for further clinical development. Our study provides mechanistic insight into how TCRs detect neoantigens and reveals the challenges in targeting KRAS-G12V mutations.

PubMed: 39030753
DOI: 10.1002/eji.202451079

Experimental method

X-RAY DIFFRACTION (1.7 Å)