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Structure of TCR and antigen complexes at an immunodominant CTL epitope in HIV-1 infection.

Shimizu A, Kawana-Tachikawa A, Yamagata A, Han C, Zhu D, Sato Y, Nakamura H, Koibuchi T, Carlson J, Martin E, Brumme CJ, Shi Y, Gao GF, Brumme ZL, Fukai S, Iwamoto A - Sci Rep (2013)

Bottom Line: Although Y135F mutation disrupted the hydrogen bond to HLA-A*2402 His70, newly formed hydrogen bond between T138 and His70 kept the conformation of the epitope in the reconstituted pMHC.TCR from Y135F- or dually-specific CTL had unique mode of binding to the mutant epitope.Y135F has been reported as a processing mutant but CTL carrying structurally adequate TCR can be found in the patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, the University of Tokyo. 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

ABSTRACT
We investigated the crystal structure of an HLA-A*2402-restricted CTL epitope in the HIV-1 nef gene (Nef134-10) before (pHLA) or after TCR docking. The wild type epitope and two escape mutants were included in the study. Y135F was an early-appearing major mutation, while F139L was a late-appearing mutation which was selected in the patients without Y135F. F139 was an eminent feature of the Nef134-10 epitope. Wild type-specific TCR was less fit to F139L mutant suggesting that F139L is an escape from the CTL against the wild type epitope. Although Y135F mutation disrupted the hydrogen bond to HLA-A*2402 His70, newly formed hydrogen bond between T138 and His70 kept the conformation of the epitope in the reconstituted pMHC. TCR from Y135F- or dually-specific CTL had unique mode of binding to the mutant epitope. Y135F has been reported as a processing mutant but CTL carrying structurally adequate TCR can be found in the patients.

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The pocket of H27-14 TCR surrounding Phe/Leu at position 6 of the Nef134-10 peptide.(a) Overlay of the H27-14 TCR-A24/Nef134-10(wt) and H27-14 TCR-A24/Nef134-10(6L). The CDR loops in the H27-14 TCR in complex with A24/Nef134-10(wt) or A24/Nef134-10(6L) are shown in cyan or yellow, respectively. The Nef134-10(wt) or Nef134-10(6L) peptides are shown in blue or orange stick models, respectively. HLA-A24 α1 but not α2 helices are shown in grey cartoon representation for clarity. (b) The side chain of Phe at P6 (stick model in blue) is surrounded by the H27-14 TCR pocket formed by the CDR loops (cyan). (c) The side chain of Leu at P6 (stick model in orange) is surrounded by the H27-14 TCR pocket formed by the CDR loops (yellow).
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f4: The pocket of H27-14 TCR surrounding Phe/Leu at position 6 of the Nef134-10 peptide.(a) Overlay of the H27-14 TCR-A24/Nef134-10(wt) and H27-14 TCR-A24/Nef134-10(6L). The CDR loops in the H27-14 TCR in complex with A24/Nef134-10(wt) or A24/Nef134-10(6L) are shown in cyan or yellow, respectively. The Nef134-10(wt) or Nef134-10(6L) peptides are shown in blue or orange stick models, respectively. HLA-A24 α1 but not α2 helices are shown in grey cartoon representation for clarity. (b) The side chain of Phe at P6 (stick model in blue) is surrounded by the H27-14 TCR pocket formed by the CDR loops (cyan). (c) The side chain of Leu at P6 (stick model in orange) is surrounded by the H27-14 TCR pocket formed by the CDR loops (yellow).

Mentions: H27-14 was slightly weaker in recognizing A24/Nef134-10(6L) than in recognizing A24/Nef134-10(wt) (Fig. 1a and Table S3). To evaluate the differences in binding ability to A24/Nef134-10(wt) or A24/Nef134-10(6L), we compared the structures of H27-14-A24/Nef134-10(wt) and H27-14-A24/Nef134-10(6L) (Fig. 4a). Conformational differences were minimal, with RMSDs of 0.485Å, 0.123Å and 0.109Å for the TCRs, Nef134-10 peptides and A24 binding clefts, respectively.


Structure of TCR and antigen complexes at an immunodominant CTL epitope in HIV-1 infection.

Shimizu A, Kawana-Tachikawa A, Yamagata A, Han C, Zhu D, Sato Y, Nakamura H, Koibuchi T, Carlson J, Martin E, Brumme CJ, Shi Y, Gao GF, Brumme ZL, Fukai S, Iwamoto A - Sci Rep (2013)

The pocket of H27-14 TCR surrounding Phe/Leu at position 6 of the Nef134-10 peptide.(a) Overlay of the H27-14 TCR-A24/Nef134-10(wt) and H27-14 TCR-A24/Nef134-10(6L). The CDR loops in the H27-14 TCR in complex with A24/Nef134-10(wt) or A24/Nef134-10(6L) are shown in cyan or yellow, respectively. The Nef134-10(wt) or Nef134-10(6L) peptides are shown in blue or orange stick models, respectively. HLA-A24 α1 but not α2 helices are shown in grey cartoon representation for clarity. (b) The side chain of Phe at P6 (stick model in blue) is surrounded by the H27-14 TCR pocket formed by the CDR loops (cyan). (c) The side chain of Leu at P6 (stick model in orange) is surrounded by the H27-14 TCR pocket formed by the CDR loops (yellow).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3818656&req=5

f4: The pocket of H27-14 TCR surrounding Phe/Leu at position 6 of the Nef134-10 peptide.(a) Overlay of the H27-14 TCR-A24/Nef134-10(wt) and H27-14 TCR-A24/Nef134-10(6L). The CDR loops in the H27-14 TCR in complex with A24/Nef134-10(wt) or A24/Nef134-10(6L) are shown in cyan or yellow, respectively. The Nef134-10(wt) or Nef134-10(6L) peptides are shown in blue or orange stick models, respectively. HLA-A24 α1 but not α2 helices are shown in grey cartoon representation for clarity. (b) The side chain of Phe at P6 (stick model in blue) is surrounded by the H27-14 TCR pocket formed by the CDR loops (cyan). (c) The side chain of Leu at P6 (stick model in orange) is surrounded by the H27-14 TCR pocket formed by the CDR loops (yellow).
Mentions: H27-14 was slightly weaker in recognizing A24/Nef134-10(6L) than in recognizing A24/Nef134-10(wt) (Fig. 1a and Table S3). To evaluate the differences in binding ability to A24/Nef134-10(wt) or A24/Nef134-10(6L), we compared the structures of H27-14-A24/Nef134-10(wt) and H27-14-A24/Nef134-10(6L) (Fig. 4a). Conformational differences were minimal, with RMSDs of 0.485Å, 0.123Å and 0.109Å for the TCRs, Nef134-10 peptides and A24 binding clefts, respectively.

Bottom Line: Although Y135F mutation disrupted the hydrogen bond to HLA-A*2402 His70, newly formed hydrogen bond between T138 and His70 kept the conformation of the epitope in the reconstituted pMHC.TCR from Y135F- or dually-specific CTL had unique mode of binding to the mutant epitope.Y135F has been reported as a processing mutant but CTL carrying structurally adequate TCR can be found in the patients.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Advanced Clinical Research Center, the Institute of Medical Science, the University of Tokyo. 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

ABSTRACT
We investigated the crystal structure of an HLA-A*2402-restricted CTL epitope in the HIV-1 nef gene (Nef134-10) before (pHLA) or after TCR docking. The wild type epitope and two escape mutants were included in the study. Y135F was an early-appearing major mutation, while F139L was a late-appearing mutation which was selected in the patients without Y135F. F139 was an eminent feature of the Nef134-10 epitope. Wild type-specific TCR was less fit to F139L mutant suggesting that F139L is an escape from the CTL against the wild type epitope. Although Y135F mutation disrupted the hydrogen bond to HLA-A*2402 His70, newly formed hydrogen bond between T138 and His70 kept the conformation of the epitope in the reconstituted pMHC. TCR from Y135F- or dually-specific CTL had unique mode of binding to the mutant epitope. Y135F has been reported as a processing mutant but CTL carrying structurally adequate TCR can be found in the patients.

Show MeSH