4WUU

Structure of ESK1 in complex with HLA-A*0201/WT1

Summary for 4WUU

• Entry DOI: 10.2210/pdb4wuu/pdb
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, ARG-MET-PHE-PRO-ASN-ALA-PRO-TYR-LEU, ... (5 entities in total)
• Functional Keywords: antibody, mhc 1, wt1, hla-a*0201, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01892; Secreted : P61769
• Total number of polymer chains: 5
• Total formula weight: 93942.25

Authors

Ataie, N.J.,Ng, H.L. (deposition date: 2014-11-03, release date: 2015-12-30, Last modification date: 2024-10-23)

Primary citation

Ataie, N.,Xiang, J.,Cheng, N.,Brea, E.J.,Lu, W.,Scheinberg, D.A.,Liu, C.,Ng, H.L.
Structure of a TCR-Mimic Antibody with Target Predicts Pharmacogenetics.
J.Mol.Biol., 428:194-205, 2016

PubMed Abstract: Antibody therapies currently target only extracellular antigens. A strategy to recognize intracellular antigens is to target peptides presented by immune HLA receptors. ESK1 is a human, T-cell receptor (TCR)-mimic antibody that binds with subnanomolar affinity to the RMF peptide from the intracellular Wilms tumor oncoprotein WT1 in complex with HLA-A*02:01. ESK1 is therapeutically effective in mouse models of WT1(+) human cancers. TCR-based therapies have been presumed to be restricted to one HLA subtype. The mechanism for the specificity and high affinity of ESK1 is unknown. We show in a crystal structure that ESK1 Fab binds to RMF/HLA-A*02:01 in a mode different from that of TCRs. From the structure, we predict and then experimentally confirm high-affinity binding with multiple other HLA-A*02 subtypes, broadening the potential patient pool for ESK1 therapy. Using the crystal structure, we also predict potential off-target binding that we experimentally confirm. Our results demonstrate how protein structure information can contribute to personalized immunotherapy.

PubMed: 26688548
DOI: 10.1016/j.jmb.2015.12.002

Experimental method

X-RAY DIFFRACTION (3.047 Å)