scholarly journals Structural variability and concerted motions of the T cell receptor - CD3 complex

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Prithvi R Pandey ◽  
Bartosz Różycki ◽  
Reinhard Lipowsky ◽  
Thomas R Weikl
Keyword(s):  
Molecular Dynamics ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
T Cell Receptor ◽  
Conformational Changes ◽  
Tilt Angle ◽  
Cell Receptor ◽  
Transmembrane Helices ◽  
Structural Variability ◽  
Dynamics Simulations

We investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) - CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR - CD3 complex, in particular in the EC interactions of the C_ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR - CD3 complex revealed in our simulations provide atomistic insights on conformational changes of the complex in response to tilt-inducing forces on antigen-bound TCRs.

scholarly journals Structural variability and concerted motions of the T cell receptor – CD3 complex

2021 ◽  
Author(s):  
Prithvi R. Pandey ◽  
Bartosz Różycki ◽  
Reinhard Lipowsky ◽  
Thomas R. Weikl
Keyword(s):  
Molecular Dynamics ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
T Cell Receptor ◽  
Tilt Angle ◽  
Structural Changes ◽  
Cell Receptor ◽  
Transmembrane Helices ◽  
Dynamics Simulations ◽  
Tcr Activation

AbstractWe investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) – CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR – CD3 complex, in particular in the EC interactions of the Cβ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR – CD3 complex revealed in our simulations provide atomistic insights for force-based models of TCR activation, which involve such structural changes in response to tilt-inducing forces on antigen-bound TCRs.

scholarly journals 4094 Structural Determinants of Immunogenicity for Peptide-Based Immunotherapy

2020 ◽  
Vol 4 (s1) ◽  
pp. 16-16
Author(s):  
Jason Devlin ◽  
Jesus Alonso ◽  
Grant Keller ◽  
Sara Bobisse ◽  
Alexandre Harari ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
Crystal Structures ◽  
T Cell Receptor ◽  
Tumor Regression ◽  
Recombinant Expression ◽  
Cell Receptor ◽  
Protein Crystal ◽  
Dynamics Simulations

OBJECTIVES/GOALS: Neoantigen vaccine immunotherapies have shown promise in clinical trials, but identifying which peptides to include in a vaccine remains a challenge. We aim to establish that molecular structural features can help predict which neoantigens to target to achieve tumor regression. METHODS/STUDY POPULATION: Proteins were prepared by recombinant expression in E. coli followed by in vitro refolding. Correctly folded proteins were purified by chromatography. Affinities of protein-protein interactions were measured by surface plasmon resonance (SPR) and thermal stabilities of proteins were determined by differential scanning fluorimetry. All experiments were performed at least in triplicate. Protein crystals were obtained by hanging drop vapor diffusion. The protein crystal structures were solved by molecular replacement and underwent several rounds of automated refinement. Molecular dynamics simulations were performed using the AMBER molecular dynamics package. RESULTS/ANTICIPATED RESULTS: A T cell receptor (TCR) expressed by tumor-infiltrating T cells exhibited a 20-fold stronger binding affinity to the neoantigen peptide compared to the self-peptide. X-ray crystal structures of the peptides with the major histocompatibility complex (MHC) protein demonstrated that a non-mutated residue in the peptide samples different positions with the mutation. The difference in conformations of the non-mutated residue was supported by molecular dynamics simulations. Crystal structures of the TCR engaging both peptide/MHCs suggested that the conformation favored by the mutant peptide was crucial for TCR binding. The TCR bound the neoantigen/MHC with faster binding kinetics. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results suggest that the mutation impacts the conformation of another residue in the peptide, and this alteration allows for more favorable T cell receptor binding to the neoantigen. This highlights the potential of non-mutated residues in contributing to neoantigen recognition.

scholarly journals Elucidating the T Cell Receptor Transmembrane Organization via Multi-Scale Molecular Dynamics Simulations

2015 ◽  
Vol 108 (2) ◽  
pp. 558a-559a
Author(s):  
Antreas C. Kalli ◽  
Andre Cohnen ◽  
Oreste Acuto ◽  
Mark S.P. Sansom
Keyword(s):  
Molecular Dynamics ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Multi Scale ◽  
Dynamics Simulations

scholarly journals Molecular Dynamics Simulations Reveal Canonical Conformations in Different pMHC/TCR Interactions

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 942 ◽  
Author(s):  
Josephine Alba ◽  
Lorenzo Di Rienzo ◽  
Edoardo Milanetti ◽  
Oreste Acuto ◽  
Marco D’Abramo
Keyword(s):  
Molecular Dynamics ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
Mhc Class I ◽  
Conformational Changes ◽  
Conformational Space ◽  
Dynamics Simulations ◽  
Β Chain

The major defense system against microbial pathogens in vertebrates is the adaptive immune response and represents an effective mechanism in cancer surveillance. T cells represent an essential component of this complex system. They can recognize myriads of antigens as short peptides (p) originated from the intracellular degradation of foreign proteins presented by major histocompatibility complex (MHC) proteins. The clonotypic T-cell antigen receptor (TCR) is specialized in recognizing pMHC and triggering T cells immune response. It is still unclear how TCR engagement to pMHC is translated into the intracellular signal that initiates T-cell immune response. Some work has suggested the possibility that pMHC binding induces in the TCR conformational changes transmitted to its companion CD3 subunits that govern signaling. The conformational changes would promote phosphorylation of the CD3 complex ζ chain that initiates signal propagation intracellularly. Here, we used all-atom molecular dynamics simulations (MDs) of 500 ns to analyze the conformational behavior of three TCRs (1G4, ILA1 and ILA1α1β1) interacting with the same MHC class I (HLA-A*02:01) bound to different peptides, and modelled in the presence of a lipid bilayer. Our data suggest a correlation between the conformations explored by the β-chain constant regions and the T-cell response experimentally determined. In particular, independently by the TCR type involved in the interaction, the TCR activation seems to be linked to a specific zone of the conformational space explored by the β-chain constant region. Moreover, TCR ligation restricts the conformational space the MHC class I groove.

scholarly journals Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region

2021 ◽  
Vol 17 (7) ◽  
pp. e1009232
Author(s):  
Dheeraj Prakaash ◽  
Graham P. Cook ◽  
Oreste Acuto ◽  
Antreas C. Kalli
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Conformational Changes ◽  
Cell Activation ◽  
Membrane Lipids ◽  
Cell Receptor ◽  
Hydrophobic Core ◽  
Cytoplasmic Tails ◽  
Dynamics Simulations

The T cell receptor (TCR-CD3) initiates T cell activation by binding to peptides of Major Histocompatibility Complexes (pMHC). The TCR-CD3 topology is well understood but the arrangement and dynamics of its cytoplasmic tails remains unknown, limiting our grasp of the signalling mechanism. Here, we use molecular dynamics simulations and modelling to investigate the entire TCR-CD3 embedded in a model membrane. Our study demonstrates conformational changes in the extracellular and transmembrane domains, and the arrangement of the TCR-CD3 cytoplasmic tails. The cytoplasmic tails formed highly interlaced structures while some tyrosines within the immunoreceptor tyrosine-based activation motifs (ITAMs) penetrated the hydrophobic core of the membrane. Interactions between the cytoplasmic tails and phosphatidylinositol phosphate lipids in the inner membrane leaflet led to the formation of a distinct anionic lipid fingerprint around the TCR-CD3. These results increase our understanding of the TCR-CD3 dynamics and the importance of membrane lipids in regulating T cell activation.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

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