Mutant NRAS Q61 neoantigen peptide-HLA-A*01:01 complex (NRAS Q61K/R-HLA-A1 complex)

The mutant NRAS Q61 neoantigen peptide-HLA complex consists of peptides derived from NRAS mutations at glutamine 61 (Q61K: ILDTAGKEEY or Q61R: ILDTAGREEY) presented by HLA-A*01:01 on cancer cell surfaces. These neoantigens arise from oncogenic NRAS Q61 mutations, which lock the GTPase in an active state by impairing GTP hydrolysis, promoting persistent signaling that drives tumor cell proliferation and survival in cancers such as melanoma and T cell lymphoma. Crystal structures of TCR N17.1.2 bound to these complexes reveal highly specific recognition, with the TCR's CDR3β loop forming a salt bridge to the exposed mutant lysine or arginine at peptide position P7 (NRAS residue 61), enabling discrimination from wild-type NRAS peptide while burying much of the peptide surface. This specificity supports T cell activation at subnanomolar peptide concentrations, as shown in functional assays and SPR binding studies. Endogenous presentation of these neoantigens has been confirmed in multiple tumor samples and cell lines via HLA peptidomics, with patient-derived TILs exhibiting cross-reactive IFN-γ responses. Therapeutic exploitation includes TCR-engineered T cells and bispecific single-chain diabodies that engage CD3 to redirect T cells for tumor killing, even at low surface neoantigen levels. These complexes represent promising targets for precision immunotherapy in HLA-A*01:01-positive patients with NRAS Q61-mutant cancers.

Other names

NRAS Q61K-HLA-A*01:01 complexNRAS Q61R-HLA-A*01:01 complexILDTAGKEEY-HLA-A*01:01 (Q61K peptide)ILDTAGREEY-HLA-A*01:01 (Q61R peptide)

TCR-mediated T cell recognition and activation\nBispecific T cell engager (scDb) binding to induce T cell cytotoxicity