Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The coordination of unprotonated peptide tertiary structure as a metric of pMHC-TCR functional avidity.

ABSTRACT: The coordination difference between the unprotonated tertiary structures of a native (Tax) peptide and a number of its variants - all peptides presented by HLA-A201 and bound to the human A6 T cell receptor-was discovered to constitute a metric of pMHC-TCR functional avidity. Moreover, increasing coordination deviations from the index were found to flag correspondingly weakening immunological outcomes of the variant peptides. The prognostic utility of the coordination difference of unprotonated tertiary structure was established to operate strictly on the peptide scale, seizing to be of relevance either to the immediate peptide environment (i.e. within the realm of peptide short range order, within 7 Å of any peptide atom) or over the entirety of the pMHC-TCR complex. Additionally, the imprint of peptide immunological identity was expressed both by the total coordination as well as by its C-C partial.

SUBMITTER: Antipas GS

PROVIDER: S-EPMC4602356 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The coordination of unprotonated peptide tertiary structure as a metric of pMHC-TCR functional avidity.

Antipas Georgios S E GS Germenis Anastasios E AE

Data in brief 20150928

The coordination difference between the unprotonated tertiary structures of a native (Tax) peptide and a number of its variants - all peptides presented by HLA-A201 and bound to the human A6 T cell receptor-was discovered to constitute a metric of pMHC-TCR functional avidity. Moreover, increasing coordination deviations from the index were found to flag correspondingly weakening immunological outcomes of the variant peptides. The prognostic utility of the coordination difference of unprotonated ...[more]

PMID: 26568977

Similar Datasets

The quantum chemical causality of pMHC-TCR biological avidity: Peptide atomic coordination data and the electronic state of agonist N termini.

Project description:The quantum state of functional avidity of the synapse formed between a peptide-Major Histocompatibility Complex (pMHC) and a T cell receptor (TCR) is a subject not previously touched upon. Here we present atomic pair correlation meta-data based on crystalized tertiary structures of the Tax (HTLV-1) peptide along with three artificially altered variants, all of which were presented by the (Class I) HLA-A201 protein in complexation with the human (CD8(+)) A6TCR. The meta-data reveal the existence of a direct relationship between pMHC-TCR functional avidity (agonist/antagonist) and peptide pair distribution function (PDF). In this context, antagonist peptides are consistently under-coordinated in respect to Tax. Moreover, Density Functional Theory (DFT) datasets in the BLYP/TZ2P level of theory resulting from relaxation of the H species on peptide tertiary structures reveal that the coordination requirement of agonist peptides is also expressed as a physical observable of the protonation state of their N termini: agonistic peptides are always found to retain a stable ammonium (NH3 (+)) terminal group while antagonist peptides are not.

| S-EPMC4510142 | biostudies-literature

The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses.

Project description:Over the past decades, adoptive transfer of T cells has revolutionized cancer immunotherapy. In particular, T-cell receptor (TCR) engineering of T cells has marked important milestones in developing more precise and personalized cancer immunotherapies. However, to get the most benefit out of this approach, understanding the role that TCR affinity, avidity, and functional avidity play on how TCRs and T cells function in the context of tumor-associated antigen (TAA) recognition is vital to keep generating improved adoptive T-cell therapies. Aside from TCR-related parameters, other critical factors that govern T-cell activation are the effect of TCR co-receptors on TCR-peptide-major histocompatibility complex (pMHC) stabilization and TCR signaling, tumor epitope density, and TCR expression levels in TCR-engineered T cells. In this review, we describe the key aspects governing TCR specificity, T-cell activation, and how these concepts can be applied to cancer-specific TCR redirection of T cells.

| S-EPMC7408146 | biostudies-literature

TCR-pMHC bond conformation controls TCR ligand discrimination.

Project description:A major unanswered question is how a TCR discriminates between foreign and self-peptides presented on the APC surface. Here, we used in situ fluorescence resonance energy transfer (FRET) to measure the distances of single TCR-pMHC bonds and the conformations of individual TCR-CD3? receptors at the membranes of live primary T cells. We found that a TCR discriminates between closely related peptides by forming single TCR-pMHC bonds with different conformations, and the most potent pMHC forms the shortest bond. The bond conformation is an intrinsic property that is independent of the binding affinity and kinetics, TCR microcluster formation, and CD4 binding. The bond conformation dictates the degree of CD3? dissociation from the inner leaflet of the plasma membrane via a positive calcium signaling feedback loop to precisely control the accessibility of CD3? ITAMs for phosphorylation. Our data revealed the mechanism by which a TCR deciphers the structural differences among peptides via the TCR-pMHC bond conformation.

| S-EPMC7052167 | biostudies-literature

TCR/pMHC Optimized Protein crystallization Screen.

Project description:The interaction between the clonotypic ?? T cell receptor (TCR), expressed on the T cell surface, and peptide-major histocompatibility complex (pMHC) molecules, expressed on the target cell surface, governs T cell mediated autoimmunity and immunity against pathogens and cancer. Structural investigations of this interaction have been limited because of the challenges inherent in the production of good quality TCR/pMHC protein crystals. Here, we report the development of an 'intelligently designed' crystallization screen that reproducibly generates high quality TCR/pMHC complex crystals suitable for X-ray crystallographic studies, thereby reducing protein consumption. Over the last 2 years, we have implemented this screen to produce 32 T cell related protein structures at high resolution, substantially contributing to the current immune protein database. Protein crystallography, used to study this interaction, has already extended our understanding of the molecular rules that govern T cell immunity. Subsequently, these data may help to guide the intelligent design of T cell based therapies that target human diseases, underlining the importance of developing optimized approaches for crystallizing novel TCR/pMHC complexes.

| S-EPMC3404460 | biostudies-literature

NMR-directed design of pre-TCR? and pMHC molecules implies a distinct geometry for pre-TCR relative to ??TCR recognition of pMHC.

Project description:The pre-T cell receptor (pre-TCR) guides early thymocytes through maturation processes within the thymus via interaction with self-ligands displayed on thymic epithelial cells. The pre-TCR is a disulfide-linked heterodimer composed of an invariant pre-TCR ? (pT?) subunit and a variable ? subunit, the latter of which is incorporated into the mature TCR in subsequent developmental progression. This interaction of pre-TCR with peptide-major histocompatibility complex (pMHC) molecules has recently been shown to drive robust pre-TCR signaling and thymocyte maturation. Although the native sequences of ? are properly folded and suitable for NMR studies in isolation, a tendency to self-associate rendered binding studies with physiological ligands difficult to interpret. Consequently, to structurally define this critical interaction, we have re-engineered the extracellular regions of ?, designated as ?-c1, for prokaryotic production to be used in NMR spectroscopy. Given the large size of the full extracellular domain of class I MHC molecules such as H-Kb, we produced a truncated form termed Kb-t harboring properties favorable for NMR measurements. This system has enabled robust measurement of a pre-TCR-pMHC interaction directly analogous to that of TCR??-pMHC. Binding surface analysis identified a contact surface comparable in size to that of the TCR??-pMHC but potentially with a rather distinct binding orientation. A tilting of the pre-TCR? when bound to the pMHC ligand recognition surface versus the upright orientation of TCR?? would alter the direction of force application between pre-TCR and TCR mechanosensors, impacting signal initiation.

| S-EPMC5777251 | biostudies-literature

PAComplex: a web server to infer peptide antigen families and binding models from TCR-pMHC complexes.

Project description:One of the most adaptive immune responses is triggered by specific T-cell receptors (TCR) binding to peptide-major histocompatibility complexes (pMHC). Despite the availability of many prediction servers to identify peptides binding to MHC, these servers are often lacking in peptide-TCR interactions and detailed atomic interacting models. PAComplex is the first web server investigating both pMHC and peptide-TCR interfaces to infer peptide antigens and homologous peptide antigens of a query. This server first identifies significantly similar TCR-pMHC templates (joint Z-value ≥ 4.0) of the query by using antibody-antigen and protein-protein interacting scoring matrices for peptide-TCR and pMHC interfaces, respectively. PAComplex then identifies the homologous peptide antigens of these hit templates from complete pathogen genome databases (≥10(8) peptide candidates from 864,628 protein sequences of 389 pathogens) and experimental peptide databases (80,057 peptides in 2287 species). Finally, the server outputs peptide antigens and homologous peptide antigens of the query and displays detailed interacting models (e.g. hydrogen bonds and steric interactions in two interfaces) of hitTCR-pMHC templates. Experimental results demonstrate that the proposed server can achieve high prediction accuracy and offer potential peptide antigens across pathogens. We believe that the server is able to provide valuable insights for the peptide vaccine and MHC restriction. The PAComplex sever is available at http://PAcomplex.life.nctu.edu.tw.

| S-EPMC3125798 | biostudies-literature

Genome-wide structural modelling of TCR-pMHC interactions.

Project description:BACKGROUND: The adaptive immune response is antigen-specific and triggered by pathogen recognition through T cells. Although the interactions and mechanisms of TCR-peptide-MHC (TCR-pMHC) have been studied over three decades, the biological basis for these processes remains controversial. As an increasing number of high-throughput binding epitopes and available TCR-pMHC complex structures, a fast genome-wide structural modelling of TCR-pMHC interactions is an emergent task for understanding immune interactions and developing peptide vaccines. RESULTS: We first constructed the PPI matrices and iMatrix, using 621 non-redundant PPI interfaces and 398 non-redundant antigen-antibody interfaces, respectively, for modelling the MHC-peptide and TCR-peptide interfaces, respectively. The iMatrix consists of four knowledge-based scoring matrices to evaluate the hydrogen bonds and van der Waals forces between sidechains or backbones, respectively. The predicted energies of iMatrix are high correlated (Pearson's correlation coefficient is 0.6) to 70 experimental free energies on antigen-antibody interfaces. To further investigate iMatrix and PPI matrices, we inferred the 701,897 potential peptide antigens with significant statistic from 389 pathogen genomes and modelled the TCR-pMHC interactions using available TCR-pMHC complex structures. These identified peptide antigens keep hydrogen-bond energies and consensus interactions and our TCR-pMHC models can provide detailed interacting models and crucial binding regions. CONCLUSIONS: Experimental results demonstrate that our method can achieve high precision for predicting binding affinity and potential peptide antigens. We believe that iMatrix and our template-based method can be useful for the binding mechanisms of TCR-pMHC complexes and peptide vaccine designs.

| S-EPMC3852114 | biostudies-literature

Information-Driven Docking for TCR-pMHC Complex Prediction.

Project description:T cell receptor (TCR) recognition of peptides presented by major histocompatibility complex (MHC) molecules is a fundamental process in the adaptive immune system. An understanding of this recognition process at the molecular level is crucial for TCR based therapeutics and vaccine design. The broad nature of TCR diversity and cross-reactivity presents a challenge for traditional structural resolution. Computational modelling of TCR-pMHC complexes offers an efficient alternative. This study compares the ability of four general-purpose docking platforms (ClusPro, LightDock, ZDOCK and HADDOCK) to make use of varying levels of binding interface information for accurate TCR-pMHC modelling. Each platform was tested on an expanded benchmark set of 44 TCR-pMHC docking cases. In general, HADDOCK is shown to be the best performer. Docking strategy guidance is provided to obtain the best models for each platform for future research. The TCR-pMHC docking cases used in this study can be downloaded from https://github.com/innate2adaptive/ExpandedBenchmark.

| S-EPMC8219952 | biostudies-literature

Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain.

Project description:Adoptive transfer of T lymphocytes transduced with a T cell receptor (TCR) to impart tumor reactivity has been reported as a potential strategy to redirect immune responses to target cancer cells (Schumacher, T.N. 2002. Nat. Rev. Immunol. 2:512-519). However, the affinity of most TCRs specific for shared tumor antigens that can be isolated is usually low. Thus, strategies to increase the affinity of TCRs or the functional avidity of TCR-transduced T cells might be therapeutically beneficial. Because glycosylation affects the flexibility, movement, and interactions of surface molecules, we tested if selectively removing conserved N-glycoslyation sites in the constant regions of TCR alpha or beta chains could increase the functional avidity of T cells transduced with such modified TCRs. We observed enhanced functional avidity and improved recognition of tumor cells by T cells harboring TCR chains with reduced N-glycosylation (DeltaTCR) as compared with T cells with wild-type (WT) TCR chains. T cells transduced with WT or DeltaTCR chains bound tetramer equivalently at 4 degrees C, but tetramer binding was enhanced at 37 degrees C, predominantly as a result of reduced tetramer dissociation. This suggested a temperature-dependent mechanism such as TCR movement in the cell surface or structural changes of the TCR allowing improved multimerization. This strategy was effective with mouse and human TCRs specific for different antigens and, thus, should be readily translated to TCRs with any specificity.

| S-EPMC2646573 | biostudies-literature

Integrating Experiment and Theory to Understand TCR-pMHC Dynamics.

Project description:The conformational dynamism of proteins is well established. Rather than having a single structure, proteins are more accurately described as a conformational ensemble that exists across a rugged energy landscape, where different conformational sub-states interconvert. The interaction between ?? T cell receptors (TCR) and cognate peptide-MHC (pMHC) is no exception, and is a dynamic process that involves substantial conformational change. This review focuses on technological advances that have begun to establish the role of conformational dynamics and dynamic allostery in TCR recognition of the pMHC and the early stages of signaling. We discuss how the marriage of molecular dynamics (MD) simulations with experimental techniques provides us with new ways to dissect and interpret the process of TCR ligation. Notably, application of simulation techniques lags behind other fields, but is predicted to make substantial contributions. Finally, we highlight integrated approaches that are being used to shed light on some of the key outstanding questions in the early events leading to TCR signaling.

| S-EPMC6293202 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data