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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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Comparisons of interaction of TCRs with pHLAs.Binding interfaces: (a) the H27-14 TCR-A24/Nef134-10(wt), (b) the T36-5 TCR-A24/Nef134-10(2F) and (c) the C1-28 TCR-A24/Nef134-10(2F). TCRs are shown as loop representations and the residues important for binding with the peptide are represented as stick models. Nef134-10(wt), blue; Nef134-10(2F), red; water molecules, green spheres; hydrogen bonds, red dashed lines; water-mediated hydrogen bonds, blue dashed lines. pHLA surface representations with the binding footprint of TCRs: (d) H27-14 TCR with the A24/Nef134-10(wt), (e) T36-5 TCR with the A24/Nef134-10(2F) and (f) C1-28 TCR with the A24/Nef134-10(2F). The surfaces of pHLA interacted with TCR are shown in green for Vα and yellow for Vβ. The CDRs on the pHLAs are represented as black loops. HLA-A24, grey; Nef134-10(wt), blue; Nef134-10(2F), red.
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f3: Comparisons of interaction of TCRs with pHLAs.Binding interfaces: (a) the H27-14 TCR-A24/Nef134-10(wt), (b) the T36-5 TCR-A24/Nef134-10(2F) and (c) the C1-28 TCR-A24/Nef134-10(2F). TCRs are shown as loop representations and the residues important for binding with the peptide are represented as stick models. Nef134-10(wt), blue; Nef134-10(2F), red; water molecules, green spheres; hydrogen bonds, red dashed lines; water-mediated hydrogen bonds, blue dashed lines. pHLA surface representations with the binding footprint of TCRs: (d) H27-14 TCR with the A24/Nef134-10(wt), (e) T36-5 TCR with the A24/Nef134-10(2F) and (f) C1-28 TCR with the A24/Nef134-10(2F). The surfaces of pHLA interacted with TCR are shown in green for Vα and yellow for Vβ. The CDRs on the pHLAs are represented as black loops. HLA-A24, grey; Nef134-10(wt), blue; Nef134-10(2F), red.

Mentions: Wild type-specific H27-14 TCR interacted with Nef134-10(wt), surrounding the F139(P6-F) residue by CDR loops (Fig. 3a, d). This complex exhibited a shape complementarity (Sc) of 0.75, which is at the higher end of the range of published TCR/pMHC17. R93α, Y98α and R31β of the H27-14 CDR rearranged to accommodate the aromatic residue of F139(P6-F) upon ligation, compared to their unligated state (Supplementary Fig. 5a, b). Y98α and R31β formed hydrogen bonds with T138(P5-T) (Supplementary Fig. 5b and Supplementary Table 3). The side chain of R93α rotated approximately 90° and formed a hydrogen bond with G100β, helping to stabilize CDRα and CDRβ at the TCR/pHLA interface.


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)

Comparisons of interaction of TCRs with pHLAs.Binding interfaces: (a) the H27-14 TCR-A24/Nef134-10(wt), (b) the T36-5 TCR-A24/Nef134-10(2F) and (c) the C1-28 TCR-A24/Nef134-10(2F). TCRs are shown as loop representations and the residues important for binding with the peptide are represented as stick models. Nef134-10(wt), blue; Nef134-10(2F), red; water molecules, green spheres; hydrogen bonds, red dashed lines; water-mediated hydrogen bonds, blue dashed lines. pHLA surface representations with the binding footprint of TCRs: (d) H27-14 TCR with the A24/Nef134-10(wt), (e) T36-5 TCR with the A24/Nef134-10(2F) and (f) C1-28 TCR with the A24/Nef134-10(2F). The surfaces of pHLA interacted with TCR are shown in green for Vα and yellow for Vβ. The CDRs on the pHLAs are represented as black loops. HLA-A24, grey; Nef134-10(wt), blue; Nef134-10(2F), red.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Comparisons of interaction of TCRs with pHLAs.Binding interfaces: (a) the H27-14 TCR-A24/Nef134-10(wt), (b) the T36-5 TCR-A24/Nef134-10(2F) and (c) the C1-28 TCR-A24/Nef134-10(2F). TCRs are shown as loop representations and the residues important for binding with the peptide are represented as stick models. Nef134-10(wt), blue; Nef134-10(2F), red; water molecules, green spheres; hydrogen bonds, red dashed lines; water-mediated hydrogen bonds, blue dashed lines. pHLA surface representations with the binding footprint of TCRs: (d) H27-14 TCR with the A24/Nef134-10(wt), (e) T36-5 TCR with the A24/Nef134-10(2F) and (f) C1-28 TCR with the A24/Nef134-10(2F). The surfaces of pHLA interacted with TCR are shown in green for Vα and yellow for Vβ. The CDRs on the pHLAs are represented as black loops. HLA-A24, grey; Nef134-10(wt), blue; Nef134-10(2F), red.
Mentions: Wild type-specific H27-14 TCR interacted with Nef134-10(wt), surrounding the F139(P6-F) residue by CDR loops (Fig. 3a, d). This complex exhibited a shape complementarity (Sc) of 0.75, which is at the higher end of the range of published TCR/pMHC17. R93α, Y98α and R31β of the H27-14 CDR rearranged to accommodate the aromatic residue of F139(P6-F) upon ligation, compared to their unligated state (Supplementary Fig. 5a, b). Y98α and R31β formed hydrogen bonds with T138(P5-T) (Supplementary Fig. 5b and Supplementary Table 3). The side chain of R93α rotated approximately 90° and formed a hydrogen bond with G100β, helping to stabilize CDRα and CDRβ at the TCR/pHLA interface.

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