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Crystal structures of high affinity human T-cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry.

Sami M, Rizkallah PJ, Dunn S, Molloy P, Moysey R, Vuidepot A, Baston E, Todorov P, Li Y, Gao F, Boulter JM, Jakobsen BK
Protein Eng Des Sel 20 397-403 (2007)
Related entries: 2p5e, 2pye, 2pyf

Cited: 40 times
EuropePMC logo PMID: 17644531

Abstract

Naturally selected T-cell receptors (TCRs) are characterised by low binding affinities, typically in the range 1-100 microM. Crystal structures of syngeneic TCRs bound to peptide major histocompatibility complex (pMHC) antigens exhibit a conserved mode of binding characterised by a distinct diagonal binding geometry, with poor shape complementarity (SC) between receptor and ligand. Here, we report the structures of three in vitro affinity enhanced TCRs that recognise the pMHC tumour epitope NY-ESO(157-165) (SLLMWITQC). These crystal structures reveal that the docking mode for the high affinity TCRs is identical to that reported for the parental wild-type TCR, with only subtle changes in the mutated complementarity determining regions (CDRs) that form contacts with pMHC; both CDR2 and CDR3 mutations act synergistically to improve the overall affinity. Comparison of free and bound TCR structures for both wild-type and a CDR3 mutant reveal an induced fit mechanism arising from restructuring of CDR3 loops which allows better peptide binding. Overall, an increased interface area, improved SC and additional H-bonding interactions are observed, accounting for the increase in affinity. Most notably, there is a marked increase in the SC for the central methionine and tryptophan peptide motif over the native TCR.

Articles - 2p5w mentioned but not cited (4)

  1. Predicting peptide binding affinities to MHC molecules using a modified semi-empirical scoring function. Liao WW, Arthur JW. PLoS One 6 e25055 (2011)
  2. DynaDom: structure-based prediction of T cell receptor inter-domain and T cell receptor-peptide-MHC (class I) association angles. Hoffmann T, Marion A, Antes I. BMC Struct Biol 17 2 (2017)
  3. Molecular Rules Underpinning Enhanced Affinity Binding of Human T Cell Receptors Engineered for Immunotherapy. Crean RM, MacLachlan BJ, Madura F, Whalley T, Rizkallah PJ, Holland CJ, McMurran C, Harper S, Godkin A, Sewell AK, Pudney CR, van der Kamp MW, Cole DK. Mol Ther Oncolytics 18 443-456 (2020)
  4. Quantitative Analysis of the Association Angle between T-cell Receptor Vα/Vβ Domains Reveals Important Features for Epitope Recognition. Hoffmann T, Krackhardt AM, Antes I. PLoS Comput Biol 11 e1004244 (2015)


Reviews citing this publication (6)

  1. The molecular basis of TCR germline bias for MHC is surprisingly simple. Garcia KC, Adams JJ, Feng D, Ely LK. Nat Immunol 10 143-147 (2009)
  2. Survey of the year 2007 commercial optical biosensor literature. Rich RL, Myszka DG. J Mol Recognit 21 355-400 (2008)
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Articles citing this publication (30)

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  2. Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes. Bulek AM, Cole DK, Skowera A, Dolton G, Gras S, Madura F, Fuller A, Miles JJ, Gostick E, Price DA, Drijfhout JW, Knight RR, Huang GC, Lissin N, Molloy PE, Wooldridge L, Jakobsen BK, Rossjohn J, Peakman M, Rizkallah PJ, Sewell AK. Nat Immunol 13 283-289 (2012)
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  4. Molecular architecture of the αβ T cell receptor-CD3 complex. Birnbaum ME, Berry R, Hsiao YS, Chen Z, Shingu-Vazquez MA, Yu X, Waghray D, Fischer S, McCluskey J, Rossjohn J, Walz T, Garcia KC. Proc Natl Acad Sci U S A 111 17576-17581 (2014)
  5. Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy. Raman MC, Rizkallah PJ, Simmons R, Donnellan Z, Dukes J, Bossi G, Le Provost GS, Todorov P, Baston E, Hickman E, Mahon T, Hassan N, Vuidepot A, Sami M, Cole DK, Jakobsen BK. Sci Rep 6 18851 (2016)
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  7. Structure-based design of a T-cell receptor leads to nearly 100-fold improvement in binding affinity for pepMHC. Haidar JN, Pierce B, Yu Y, Tong W, Li M, Weng Z. Proteins 74 948-960 (2009)
  8. Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose. Lever M, Lim HS, Kruger P, Nguyen J, Trendel N, Abu-Shah E, Maini PK, van der Merwe PA, Dushek O. Proc Natl Acad Sci U S A 113 E6630-E6638 (2016)
  9. T-cell receptor (TCR)-peptide specificity overrides affinity-enhancing TCR-major histocompatibility complex interactions. Cole DK, Miles KM, Madura F, Holland CJ, Schauenburg AJ, Godkin AJ, Bulek AM, Fuller A, Akpovwa HJ, Pymm PG, Liddy N, Sami M, Li Y, Rizkallah PJ, Jakobsen BK, Sewell AK. J Biol Chem 289 628-638 (2014)
  10. T cell receptor engagement of peptide-major histocompatibility complex class I does not modify CD8 binding. Cole DK, Dunn SM, Sami M, Boulter JM, Jakobsen BK, Sewell AK. Mol Immunol 45 2700-2709 (2008)
  11. Structure of a TCR-Mimic Antibody with Target Predicts Pharmacogenetics. Ataie N, Xiang J, Cheng N, Brea EJ, Lu W, Scheinberg DA, Liu C, Ng HL. J Mol Biol 428 194-205 (2016)
  12. Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA. Holland CJ, Crean RM, Pentier JM, de Wet B, Lloyd A, Srikannathasan V, Lissin N, Lloyd KA, Blicher TH, Conroy PJ, Hock M, Pengelly RJ, Spinner TE, Cameron B, Potter EA, Jeyanthan A, Molloy PE, Sami M, Aleksic M, Liddy N, Robinson RA, Harper S, Lepore M, Pudney CR, van der Kamp MW, Rizkallah PJ, Jakobsen BK, Vuidepot A, Cole DK. J Clin Invest 130 2673-2688 (2020)
  13. T-cell receptor specificity maintained by altered thermodynamics. Madura F, Rizkallah PJ, Miles KM, Holland CJ, Bulek AM, Fuller A, Schauenburg AJ, Miles JJ, Liddy N, Sami M, Li Y, Hossain M, Baker BM, Jakobsen BK, Sewell AK, Cole DK. J Biol Chem 288 18766-18775 (2013)
  14. Distinct sets of alphabeta TCRs confer similar recognition of tumor antigen NY-ESO-1157-165 by interacting with its central Met/Trp residues. Derré L, Bruyninx M, Baumgaertner P, Ferber M, Schmid D, Leimgruber A, Zoete V, Romero P, Michielin O, Speiser DE, Rufer N. Proc Natl Acad Sci U S A 105 15010-15015 (2008)
  15. TCRs with Distinct Specificity Profiles Use Different Binding Modes to Engage an Identical Peptide-HLA Complex. Coles CH, Mulvaney RM, Malla S, Walker A, Smith KJ, Lloyd A, Lowe KL, McCully ML, Martinez Hague R, Aleksic M, Harper J, Paston SJ, Donnellan Z, Chester F, Wiederhold K, Robinson RA, Knox A, Stacey AR, Dukes J, Baston E, Griffin S, Jakobsen BK, Vuidepot A, Harper S. J Immunol 204 1943-1953 (2020)
  16. Identification and engineering of human variable regions that allow expression of stable single-chain T cell receptors. Aggen DH, Chervin AS, Insaidoo FK, Piepenbrink KH, Baker BM, Kranz DM. Protein Eng Des Sel 24 361-372 (2011)
  17. Increased Peptide Contacts Govern High Affinity Binding of a Modified TCR Whilst Maintaining a Native pMHC Docking Mode. Cole DK, Sami M, Scott DR, Rizkallah PJ, Borbulevych OY, Todorov PT, Moysey RK, Jakobsen BK, Boulter JM, Baker BM, Yi Li. Front Immunol 4 168 (2013)
  18. TCR/pMHC Optimized Protein crystallization Screen. Bulek AM, Madura F, Fuller A, Holland CJ, Schauenburg AJ, Sewell AK, Rizkallah PJ, Cole DK. J Immunol Methods 382 203-210 (2012)
  19. TCR-induced alteration of primary MHC peptide anchor residue. Madura F, Rizkallah PJ, Legut M, Holland CJ, Fuller A, Bulek A, Schauenburg AJ, Trimby A, Hopkins JR, Wells SA, Godkin A, Miles JJ, Sami M, Li Y, Liddy N, Jakobsen BK, Loveridge EJ, Cole DK, Sewell AK. Eur J Immunol 49 1052-1066 (2019)
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  21. Human cytomegalovirus-specific T-cell receptor engineered for high affinity and soluble expression using mammalian cell display. Wagner EK, Qerqez AN, Stevens CA, Nguyen AW, Delidakis G, Maynard JA. J Biol Chem 294 5790-5804 (2019)
  22. T cell receptor interactions with human leukocyte antigen govern indirect peptide selectivity for the cancer testis antigen MAGE-A4. Coles CH, McMurran C, Lloyd A, Hock M, Hibbert L, Raman MCC, Hayes C, Lupardus P, Cole DK, Harper S. J Biol Chem 295 11486-11494 (2020)
  23. Combinations of affinity-enhancing mutations in a T cell receptor reveal highly nonadditive effects within and between complementarity determining regions and chains. Pierce BG, Haidar JN, Yu Y, Weng Z. Biochemistry 49 7050-7059 (2010)
  24. T-cell receptors binding orientation over peptide/MHC class I is driven by long-range interactions. Ferber M, Zoete V, Michielin O. PLoS One 7 e51943 (2012)
  25. Identification of NY-ESO-1157-165 Specific Murine T Cell Receptors With Distinct Recognition Pattern for Tumor Immunotherapy. Zhang H, Sun M, Wang J, Zeng B, Cao X, Han Y, Tan S, Gao GF. Front Immunol 12 644520 (2021)
  26. Structural and Thermodynamic Basis of the Enhanced Interaction between Kinesin Spindle Protein Eg5 and STLC-type Inhibitors. Yokoyama H, Sawada JI, Sato K, Ogo N, Kamei N, Ishikawa Y, Hara K, Asai A, Hashimoto H. ACS Omega 3 12284-12294 (2018)
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  28. Characterization of amino acid residues of T-cell receptors interacting with HLA-A*02-restricted antigen peptides. Zhu Y, Huang C, Su M, Ge Z, Gao L, Shi Y, Wang X, Chen J. Ann Transl Med 9 495 (2021)
  29. Structures of the antibody 64M-5 Fab and its complex with dT(6-4)T indicate induced-fit and high-affinity mechanisms. Yokoyama H, Mizutani R, Noguchi S, Hayashida N. Acta Crystallogr F Struct Biol Commun 75 80-88 (2019)
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