9FE1
Cryo-EM structure of the ternary DARPin NY_1/HLA-A0201/NY-ESO1 complex.
Summary for 9FE1
| Entry DOI | 10.2210/pdb9fe1/pdb |
| Related | 9EPA |
| EMDB information | 50336 |
| Descriptor | MHC class I antigen, Beta-2-microglobulin, Cancer/testis antigen 1, ... (4 entities in total) |
| Functional Keywords | darpin targeting mhc molecules in complex with tumor-associated peptide antigens, immune system |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 65106.96 |
| Authors | Schulte, T.,Wallden, K.,Carroni, M.,Sandalova, T.,Walser, M.,Mueller, S.,Venetz, N.,Achour, A. (deposition date: 2024-05-17, release date: 2025-05-28, Last modification date: 2025-12-10) |
| Primary citation | Venetz-Arenas, N.,Schulte, T.,Muller, S.,Wallden, K.,Fischer, S.,Resink, T.,Kadri, N.,Paladino, M.,Pina, N.,Radom, F.,Villemagne, D.,Bruckmaier, S.,Cornelius, A.,Hospodarsch, T.,Alici, E.,Ljunggren, H.G.,Chambers, B.J.,Han, X.,Sun, R.,Carroni, M.,Levitsky, V.,Sandalova, T.,Walser, M.,Achour, A. Development of DARPin T cell engagers for specific targeting of tumor-associated HLA/peptide complexes. Iscience, 28:113926-113926, 2025 Cited by PubMed Abstract: The balance between affinity and specificity in T cell receptor (TCR)-dependent targeting of HLA-restricted tumor-associated antigens presents a significant challenge for immunotherapy development. T cell engagers that circumvent these limitations are therefore of particular interest. We established a process to generate bispecific designed ankyrin repeat proteins (DARPins) that simultaneously target HLA-I/peptide complexes and CD3e. These high-affinity T cell engagers elicited CD8 T cell activation against tumor targets with strong peptide specificity, as confirmed by X-scanning mutagenesis and functional killing assays. A cryo-EM structure of the ternary DARPin/HLA-A∗0201/NY-ESO1 complex revealed a rigid, concave DARPin surface spanning the full length of the peptide-binding cleft, contacting both α-helices and the peptide. The present findings reveal promising immuno-oncotherapeutic approaches and demonstrate the feasibility of rapidly developing DARPins with high affinity and specificity for HLA/peptide targets, which can be readily combined with a new generation of anti-CD3e-specific DARPins. PubMed: 41321628DOI: 10.1016/j.isci.2025.113926 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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