9NMX

TCR156 S32Malpha variant bound to HLA A*02:01-PAP

Summary for 9NMX

• Entry DOI: 10.2210/pdb9nmx/pdb
• Related: 9NMU 9NMV 9NMW 9NMY
• Descriptor: HLA class I histocompatibility antigen, A alpha chain, Beta-2-microglobulin, Prostatic acid phosphatase, ... (10 entities in total)
• Functional Keywords: complex, tcr, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 109892.89

Authors

Jude, K.M.,Chen, X.,Garcia, K.C. (deposition date: 2025-03-04, release date: 2026-03-18, Last modification date: 2026-04-29)

Primary citation

Chen, X.,Mao, Z.,Kolawole, E.M.,Persechino, M.,Jude, K.M.,Ogishi, M.,Mo, K.C.,McLaughlin, J.,Cheng, D.,Xiang, X.,Yang, X.,Gee, C.,Liu, S.,Yang, A.,Obenaus, M.,Wang, N.,Noguchi, M.,Stoyanova, T.,Lee, J.K.,Good, Z.,Latorraca, N.R.,Evavold, B.D.,Witte, O.N.,Garcia, K.C.
Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering.
Science, 391:eadx3162-eadx3162, 2026

PubMed Abstract: T cells are often weakly responsive to tumor self-antigens because of central tolerance, constraining their ability to eliminate tumors. We exploited mechanical force to engineer a weakly reactive T cell receptor (TCR) specific for a nonmutated tumor-associated antigen (TAA), prostatic acid phosphatase (PAP). We identified a catch-bonding "hotspot" whose mutation enhanced T cell activity by increasing TCR-pMHC (peptide-major histocompatibility complex) bond lifetime while preserving physiological affinities and antigen fine specificities. T cells expressing these engineered TCRs showed vastly superior expansion in the tumor, effector phenotypes, and tumor elimination. Crystal structures and molecular dynamics simulations revealed a single amino acid mutation at the catch-bond hotspot primes the TCR for peptide interaction through water reorganization at the TCR-pMHC interface. Catch-bond engineering is a viable biophysically based strategy for transforming tolerized antitumor T cells into potent TCR-T cell therapy killers.

PubMed: 41855322
DOI: 10.1126/science.adx3162

Experimental method

X-RAY DIFFRACTION (2.19 Å)