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Science 11 October 1996:
Vol. 274. no. 5285, pp. 209 - 219
DOI: 10.1126/science.274.5285.209
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Research Articles

An alpha beta T Cell Receptor Structure at 2.5 Å and Its Orientation in the TCR-MHC Complex

K. Christopher Garcia, Massimo Degano, Robyn L. Stanfield, Anders Brunmark, Michael R. Jackson, Per A. Peterson, Luc Teyton, Ian A. Wilson *

The central event in the cellular immune response to invading microorganisms is the specific recognition of foreign peptides bound to major histocompatibility complex (MHC) molecules by the alpha beta T cell receptor (TCR). The x-ray structure of the complete extracellular fragment of a glycosylated alpha beta TCR was determined at 2.5 angstroms, and its orientation bound to a class I MHC-peptide (pMHC) complex was elucidated from crystals of the TCR-pMHC complex. The TCR resembles an antibody in the variable Valpha and Vbeta domains but deviates in the constant Calpha domain and in the interdomain pairing of Calpha with Cbeta . Four of seven possible asparagine-linked glycosylation sites have ordered carbohydrate moieties, one of which lies in the Calpha -Cbeta interface. The TCR combining site is relatively flat except for a deep hydrophobic cavity between the hypervariable CDR3s (complementarity-determining regions) of the alpha  and beta  chains. The 2C TCR covers the class I MHC H-2Kb binding groove so that the Valpha CDRs 1 and 2 are positioned over the amino-terminal region of the bound dEV8 peptide, the Vbeta chain CDRs 1 and 2 are over the carboxyl-terminal region of the peptide, and the Valpha and Vbeta CDR3s straddle the peptide between the helices around the central position of the peptide.

K. C. Garcia, M. Degano, R. L. Stanfield, and I. A. Wilson are at the Department of Molecular Biology and the Skaggs Institute of Chemical Biology, Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. A. Brunmark, M. R. Jackson, P. A. Peterson, and L. Teyton are at the R. W. Johnson Pharmaceutical Research Institute-La Jolla, 3535 General Atomic Court, San Diego, CA 92121, USA.
*   To whom all correspondence should be addressed. E-mail: wilson{at}scripps.edu

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Human CD8 co-receptor is strictly involved in MHC-peptide tetramer-TCR binding and T cell activation.
R. Campanelli, B. Palermo, S. Garbelli, S. Mantovani, P. Lucchi, A. Necker, E. Lantelme, and C. Giachino (2002)
Int. Immunol. 14, 39-44
   Abstract »    Full Text »    PDF »
The Transporter Associated With Antigen Processing: Function and Implications in Human Diseases.
B. Lankat-Buttgereit and R. Tampe (2002)
Physiol Rev 82, 187-204
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How H13 Histocompatibility Peptides Differing by a Single Methyl Group and Lacking Conventional MHC Binding Anchor Motifs Determine Self-Nonself Discrimination.
D. A. Ostrov, M. M. Roden, W. Shi, E. Palmieri, G. J. Christianson, L. Mendoza, G. Villaflor, D. Tilley, N. Shastri, H. Grey, et al. (2002)
J. Immunol. 168, 283-289
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Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load.
S. L. Silins, M. A. Sherritt, J. M. Silleri, S. M. Cross, S. L. Elliott, M. Bharadwaj, T. T. T. Le, L. E. Morrison, R. Khanna, D. J. Moss, et al. (2001)
Blood 98, 3739-3744
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T Cell Activity Correlates with Oligomeric Peptide-Major Histocompatibility Complex Binding on T Cell Surface.
J. Buslepp, R. Zhao, D. Donnini, D. Loftus, M. Saad, E. Appella, and E. J. Collins (2001)
J. Biol. Chem. 276, 47320-47328
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Peptide Length Variants p2Ca and QL9 Present Distinct Conformations to Ld-Specific T Cells.
T. M. C. Hornell, S. M. Martin, N. B. Myers, and J. M. Connolly (2001)
J. Immunol. 167, 4207-4214
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Immunobiological Analysis of TCR Single-Chain Transgenic Mice Reveals New Possibilities for Interaction between CDR3{alpha} and an Antigenic Peptide Bound to MHC Class I.
W. Zhang, S. Honda, F. Wang, T. P. DiLorenzo, A. M. Kalergis, D. A. Ostrov, and S. G. Nathenson (2001)
J. Immunol. 167, 4396-4404
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Low-Avidity Self-Specific T Cells Display a Pronounced Expansion Defect That Can Be Overcome by Altered Peptide Ligands.
K. E. de Visser, T. A. Cordaro, H. W. H. G. Kessels, F. H. Tirion, T. N. M. Schumacher, and A. M. Kruisbeek (2001)
J. Immunol. 167, 3818-3828
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Antibody Catalysis of the Oxidation of Water.
P. Wentworth Jr., L. H. Jones, A. D. Wentworth, X. Zhu, N. A. Larsen, I. A. Wilson, X. Xu, W. A. Goddard III, K. D. Janda, A. Eschenmoser, et al. (2001)
Science 293, 1806-1811
   Abstract »    Full Text »    PDF »
Identification of Key Amino Acids of the Mouse Mammary Tumor Virus Superantigen Involved in the Specific Interaction with T-Cell Receptor V{beta} Domains.
F. Baribaud, S. Wirth, I. Maillard, S. Valsesia, H. Acha-Orbea, and H. Diggelmann (2001)
J. Virol. 75, 7453-7461
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Combinatorial Peptide Libraries and Biometric Score Matrices Permit the Quantitative Analysis of Specific and Degenerate Interactions Between Clonotypic TCR and MHC Peptide Ligands.
Y. Zhao, B. Gran23, C. Pinilla, S. Markovic-Plese, B. Hemmer, A. Tzou, L. W. Whitney, W. E. Biddison, R. Martin, and R. Simon (2001)
J. Immunol. 167, 2130-2141
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Presidential Address to The American Association of Immunologists : Major Histocompatibility Complex Proteins and TCRs: Do They Really Go Together Like a Horse and Carriage?.
P. Marrack, J. Bender, M. Jordan, W. Rees, J. Robertson, B. C. Schaefer, and J. Kappler (2001)
J. Immunol. 167, 617-621
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Expansion of the Antigenic Repertoire of a Single T Cell Receptor upon T Cell Activation.
A. Amrani, P. Serra, J. Yamanouchi, J. D. Trudeau, R. Tan, J. F. Elliott, and P. Santamaria (2001)
J. Immunol. 167, 655-666
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Degeneracy and additional alloreactivity of drug-specific human {{alpha}}{beta}+ T cell clones.
S. von Greyerz, G. Bultemann, K. Schnyder, C. Burkhart, B. Lotti, Y. Hari, and W. J. Pichler (2001)
Int. Immunol. 13, 877-885
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The flexibility of the TCR allows recognition of a large set of naturally occurring epitope variants by HIV-specific cytotoxic T lymphocytes.
F. Buseyne and Y. Riviere (2001)
Int. Immunol. 13, 941-950
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Kinetics and thermodynamics of T cell receptor- autoantigen interactions in murine experimental autoimmune encephalomyelitis.
K. C. Garcia, C. G. Radu, J. Ho, R. J. Ober, and E. S. Ward (2001)
PNAS 98, 6818-6823
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Requirement for a Complex Array of Costimulators in the Negative Selection of Autoreactive Thymocytes In Vivo.
R. Li and D. M. Page (2001)
J. Immunol. 166, 6050-6056
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Glycosylation and the Immune System.
P. M. Rudd, T. Elliott, P. Cresswell, I. A. Wilson, and R. A. Dwek (2001)
Science 291, 2370-2376
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Two MHC Surface Amino Acid Differences Distinguish Foreign Peptide Recognition from Autoantigen Specificity.
D. Basu, S. Horvath, L. O'Mara, D. Donermeyer, and P. M. Allen (2001)
J. Immunol. 166, 4005-4011
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Identification of a Crucial Energetic Footprint on the {alpha}1 Helix of Human Histocompatibility Leukocyte Antigen (Hla)-A2 That Provides Functional Interactions for Recognition by Tax Peptide/Hla-A2-Specific T Cell Receptors.
B. M. Baker, R. V. Turner, S. J. Gagnon, D. C. Wiley, and W. E. Biddison (2001)
J. Exp. Med. 193, 551-562
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