Comparative analysis of <scp>CDR</scp>3 regions in paired human αβ <scp>CD</scp>8 T cells

Yu, Kun; Shi, Jingwei; Lü, Dan; Yang, Qiong

doi:10.1002/2211-5463.12690

Cited by 12 publications

(11 citation statements)

References 46 publications

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“…Additionally, a characterization of structure and dynamics of a TCR is essential to elucidate the antigen-binding mechanism, the involved conformational changes and the associated biological implications ( 4 , 17 , 18 ). X-ray studies comparing TCRs crystallized with and without the pMHC complex revealed a high flexibility in the binding interface ( 1 , 3 , 14 , 17 , 20 ). However, crystal structures represent only a snapshot of a specific protein conformation that can be distorted due to crystal packing effects ( 15 , 59 ).…”

Section: Discussionmentioning

confidence: 99%

“…A possible assignment of the crystal structures to kinetic macrostates in solution is shown in Figure 6 for the CDR3ß loop. Various studies focused on characterizing the role of the CDR3 loops and identified strong structural loop correlations in the peptide recognition process ( 13 , 14 , 19 ). As evidence for a structural correlation of the CDR3 loops has been provided, we reconstructed thermodynamics and kinetics for the combined CDR3 loops.…”

Section: Discussionmentioning

confidence: 99%

“…The CDR3 loops are located in the center of the paratope and play a crucial role in the peptide recognition ( 12 ). Additionally, the CDR3 loops have been discussed to directly influence each other and to be structurally correlated ( 13 , 14 ). Analogous to antibodies five of the six CDR loops adopt a limited set of main-chain conformations, so called canonical structures.…”

Section: Introductionmentioning

confidence: 99%

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T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions

et al. 2020

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T-cell receptors are an important part in the adaptive immune system as they are responsible for detecting foreign proteins presented by the major histocompatibility complex (MHC). The affinity is predominantly determined by structure and sequence of the complementarity determining regions (CDRs), of which the CDR3 loops are responsible for peptide recognition. We present a kinetic classification of T-cell receptor CDR3 loops with different loop lengths into canonical and non-canonical solution structures. Using molecular dynamics simulations, we do not only sample available X-ray structures, but we also observe a substantially broader CDR3 loop ensemble with various distinct kinetic minima in solution. Our results strongly imply, that for given CDR3 loop sequences several canonical structures have to be considered to characterize the conformational diversity of these loops. Our suggested dominant solution structures could extend the repertoire of available canonical clusters by including kinetic minimum structures present in solution. Thus, the CDR3 loops need to be characterized as conformational ensembles in solution. Furthermore, the conformational changes of the CDR3 loops follow the paradigm of conformational selection, because the experimentally determined binding competent state is present within this ensemble of pre-existing conformations without the presence of the antigen. We also identify strong correlations between the CDR3 loops and include combined state descriptions. Additionally, we observe a strong dependency of the CDR3 loop conformations on the relative Vα-Vβ interdomain orientations, revealing that certain CDR3 loop states favor specific interface orientations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions

et al. 2020

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“…Among the AAs with a higher frequency in all NCs were threonine and tyrosine, which are both polar hydrophilic residues. Apart from NCs, a general trend that was recorded regarding the most frequent clonotypes post-RT was the enrichment of CDR3 with polar and/or acidic AAs, which has been found to contribute to the TCR bonding process and may be related to the restricted localization of TCR on HLA-A2 ( 25 ). Notably, it has previously been shown that the nature of AA residues (especially at position 109) within the CDR3 has a crucial role for T-cell autoreactivity, which increases significantly in the presence of hydrophobic residues ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

The impact of radiation therapy on the TCR Vβ chain repertoire in patients with prostate cancer

Goulielmaki

Davanos²,

Kogionou

et al. 2022

Int J Oncol

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Radiation therapy (RT) is an essential component in the therapeutic treatment of patients with localized prostate cancer (LPCa). Besides its local effects, ionizing radiation has been linked to mechanisms leading to systemic immune activation. The present study explored the effect of RT on the T-cell receptor variable β (TCR Vβ) chain repertoire of peripheral blood T cells in patients with LPCa. High-throughput TCR Vβ sequencing was performed on 20 blood samples collected from patients with LPCa at baseline and 3 months post-RT. The diversity index was altered, as were TCR Vβ clonal evenness and convergence before and post-RT; however, these findings were not significant. Notably, marked changes in the frequencies among the top 10 TCR Vβ clonotypes were detected and some patients developed new clonotypes of high abundance. These data provided initial evidence that RT in patients with LPCa may induce systemic immune changes, which could be exploited by future therapies for improved clinical results.

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“…The enrichment of negative charges in the TCR binding loop, especially the germline loop encoded by the TCRVα and Vβ genes, enables this to occur and is related to the restricted localization of TCR on HLA-A2 (73). Yu et al also found that the bicyclic loops of TCR α and β chains contain many charged polar residues (73). The amino acids in the CDR3 loop region located on the TCR α and β chains are significantly different, and each chain has a special role in recognizing the antigen-MHC complex.…”

Section: Discussionmentioning

confidence: 99%

Characterization of amino acid residues of T-cell receptors interacting with HLA-A*02-restricted antigen peptides

Zhu¹,

Huang²,

Su³

et al. 2021

Ann Transl Med

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Background: The present study aimed to explore residues' properties interacting with HLA-A*02restricted peptides on T-cell receptors (TCRs) and their effects on bond types of interaction and binding free energy.Methods: We searched the crystal structures of HLA-A*02-restricted peptide-TCR complexes from the Protein Data Bank (PDB) database and subsequently collected relevant parameters. We then employed Schrodinger to analyze the bond types of interaction and Gromacs 2019 to evaluate the TCR-antigen peptide complex's molecular dynamics simulation. Finally, we compared the changes of bond types of interaction and binding free energy before and after residue substitution to ensure consistency of the conditions before and after residue substitution. Results:The main sites on the antigen peptides that formed the intermolecular interaction [hydrogen bond (HB) and pi stack] with TCRs were P4, P8, P2, and P6. The hydrophobicity of the amino acids inside or outside the disulfide bond of TCRs may be related to the intermolecular interaction and binding free energy between TCRs and peptides. Residues located outside the disulfide bond of TCR α or β chains and forming pi stack force played favorable roles in the complex intermolecular interaction and binding free energy. The residues of the TCR α or β chains that interacted with peptides were replaced by alanine (Ala) or glycine (Gly), and their intermolecular binding free energy of the complex had been improved. However, it had nothing to do with the formation of HB. Conclusions:The findings of this study suggest that the hydrophobic nature of the amino acids inside or outside the disulfide bonds on the TCR may be associated with the intermolecular interaction and binding between the TCR and polypeptide. The residues located outside the TCR α or β single-chain disulfide bond and forming the pi-stack force showed a beneficial effect on the intermolecular interaction and binding of the complex. In addition, the part of the residues on the TCR α or β single chain that produced bond types of interaction with the polypeptide after being replaced by Ala or Gly, the intermolecular binding free energy of the complex was increased, regardless of whether HB was formed.

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Comparative analysis of CDR3 regions in paired human αβ CD8 T cells

Cited by 12 publications

References 46 publications

T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions

T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions

The impact of radiation therapy on the TCR Vβ chain repertoire in patients with prostate cancer

Characterization of amino acid residues of T-cell receptors interacting with HLA-A*02-restricted antigen peptides

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