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

Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE

Original Publication: [Lausanne : Frontiers Research Foundation]

Complementarity Determining Regions/*chemistry ; Receptors, Antigen, T-Cell, alpha-beta/*chemistry; Adaptive Immunity ; Animals ; Antigens/metabolism ; Complementarity Determining Regions/genetics ; Complementarity Determining Regions/metabolism ; Crystallography, X-Ray ; Histocompatibility Antigens/metabolism ; Humans ; Molecular Dynamics Simulation ; Peptides/metabolism ; Protein Binding ; Protein Conformation ; Protein Domains/genetics ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; Receptors, Antigen, T-Cell, alpha-beta/metabolism ; Structure-Activity Relationship ; T-Cell Antigen Receptor Specificity

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.
(Copyright © 2020 Fernández-Quintero, Pomarici, Loeffler, Seidler and Liedl.)

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P 30565 Austria FWF_ Austrian Science Fund FWF; P 30737 Austria FWF_ Austrian Science Fund FWF

Keywords: CDR3 loop ensembles; Markov-state models; T-cell receptor structure and design; T-cell receptors; conformational selection; relative Vα/Vβ domain distributions

0 (Antigens)
0 (Complementarity Determining Regions)
0 (Histocompatibility Antigens)
0 (Peptides)
0 (Receptors, Antigen, T-Cell, alpha-beta)

Date Created: 20200801 Date Completed: 20210426 Latest Revision: 20240214

20240214

PMC7360859

10.3389/fimmu.2020.01440

32733478