4JFF

Preservation of peptide specificity during TCR-MHC contact dominated affinity enhancement of a melanoma-specific TCR

Summary for 4JFF

• Entry DOI: 10.2210/pdb4jff/pdb
• Related: 4JFD 4JFE 4JFH 4JFO 4JFP 4JFQ
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, Melanoma motif, ... (8 entities in total)
• Functional Keywords: hla, tcr, melanoma motif, immune system, high affinity
• 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: 95374.64

Authors

Rizkallah, P.J.,Cole, D.K.,Madura, F.,Sewell, A.K. (deposition date: 2013-02-28, release date: 2013-05-29, Last modification date: 2024-10-16)

Primary citation

Madura, F.,Rizkallah, P.J.,Miles, K.M.,Holland, C.J.,Bulek, A.M.,Fuller, A.,Schauenburg, A.J.,Miles, J.J.,Liddy, N.,Sami, M.,Li, Y.,Hossain, M.,Baker, B.M.,Jakobsen, B.K.,Sewell, A.K.,Cole, D.K.
T-cell receptor specificity maintained by altered thermodynamics.
J.Biol.Chem., 288:18766-18775, 2013

PubMed Abstract: The T-cell receptor (TCR) recognizes peptides bound to major histocompatibility molecules (MHC) and allows T-cells to interrogate the cellular proteome for internal anomalies from the cell surface. The TCR contacts both MHC and peptide in an interaction characterized by weak affinity (KD = 100 nM to 270 μM). We used phage-display to produce a melanoma-specific TCR (α24β17) with a 30,000-fold enhanced binding affinity (KD = 0.6 nM) to aid our exploration of the molecular mechanisms utilized to maintain peptide specificity. Remarkably, although the enhanced affinity was mediated primarily through new TCR-MHC contacts, α24β17 remained acutely sensitive to modifications at every position along the peptide backbone, mimicking the specificity of the wild type TCR. Thermodynamic analyses revealed an important role for solvation in directing peptide specificity. These findings advance our understanding of the molecular mechanisms that can govern the exquisite peptide specificity characteristic of TCR recognition.

PubMed: 23698002
DOI: 10.1074/jbc.M113.464560

Experimental method

X-RAY DIFFRACTION (2.43 Å)