Integrating Experiment and Theory to Understand TCR-pMHC Dynamics

Buckle, Ashley M.; Borg, Natalie A.

doi:10.3389/fimmu.2018.02898

Cited by 26 publications

(19 citation statements)

References 131 publications

(107 reference statements)

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“…Our MD data suggests HLA-B*57:01bound peptides bearing abacavir-compatible PΩ residues adopt a highly diverse range of conformations when abacavir is bound, and that these altered conformations also play a role in abacavir-induced T cell activation. The intricacy of the short-and long-lived interactions between the TCR and HLA-B*57:01-peptide is consistent with the role of conformational dynamics in the activation of the immune system [17][18][19][20][21][22][23] . The TCR scans a wide range of conformations in each system existing in a conformational ensemble.…”

Section: Abacavir Is Highly Dynamic When Lodged Between Hla-b*57:01 Asupporting

confidence: 70%

The Role of Conformational Dynamics in abacavir-Induced Hypersensitivity Syndrome

Kass

Fodor

Riley

et al. 2017

Preprint

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Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS).However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir's specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots.Further, the presence of abacavir has a direct impact on the dynamics and the conformational space available to peptides bound to HLA-B*57:01, likely influencing abacavir-induced immune self-reactivity. Our results support hypersensitivity models in which abacavir-binding alters the equilibrium proportions of neopeptide conformations in a manner favourable to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.

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Section: Abacavir Is Highly Dynamic When Lodged Between Hla-b*57:01 Asupporting

confidence: 70%

The Role of Conformational Dynamics in abacavir-Induced Hypersensitivity Syndrome

Kass

Fodor

Riley

et al. 2017

Preprint

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“…The Asp116His polymorphism is thus not only linked to AS, but also to HC flexibility. MD simulations support these results and further suggest that HC dynamics and the conformational plasticity of natural peptide ligands influence each other (45,47,(49)(50)(51)(52). Although all MD simulations performed in the context of these studies indicate a higher flexibility of the B2705 F-pocket, one could argue that they examine rather limited time spans, "several orders of magnitude shorter than more biologically relevant timescales, " as pointed out by Buckle and Borg (53), indicating a need for additional dynamics-directed experimental studies.…”

Section: Discussionsupporting

confidence: 53%

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

et al. 2020

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The development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self-peptides could promote T cell cross-reactivity. A pair of class I subtypes, HLA-B2705 and HLA-B2709, have previously been intensely studied, because they are distinguished from each other only by a single amino acid exchange at the floor of the peptide-binding groove, yet are differentially associated with the autoinflammatory disorder ankylosing spondylitis. Using X-ray crystallography in combination with ensemble refinement, we find that the non-disease-associated subtype HLA-B2709, when presenting the self-peptide pGR (RRRWHRWRL), exhibits elevated conformational dynamics, and the complex can also be recognized by T cells. Both features are not observed in case of the sequence-related self-peptide pVIPR (RRKWRRWHL) in complex with this subtype, and T cell cross-reactivity between pGR, pVIPR, and the viral peptide pLMP2 (RRRWRRLTV) is only rarely observed. The disease-associated subtype HLA-B2705, however, exhibits extensive conformational flexibility in case of the three complexes, all of which are also recognized by frequently occurring cross-reactive T cells. A comparison of the structural and dynamic properties of the six HLA-B27 complexes, together with their individual ability to interact with T cells, permits us to correlate the flexibility of HLA-B27 complexes with effector cell reactivity. The results suggest the existence of an inverse relationship between conformational plasticity of peptide-HLA-B27 complexes and the efficiency of negative selection of self-reactive cells within the thymus.

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“…50]. Recently, 'ensemble refinement' of crystal data with MD simulations has suggested conformational diversity in the microsecond range, but the conformational changes implicated here-in would be on the millisecond to minutes scale; in this regard, NMR of membrane-bound receptors may offer promise [50][51][52][53][54] Finally, a dynamics mechanism driven by H-bonding networks is consistent with the knowledge that different T-cell dose-response curves are found at the same TCR affinity for the same pMHC [40,[55][56][57][58]. Even if we assume similar TCR-affinity for the three 4OZ structures, it appears that somatic selection directly effects H-bonds implicated in V-domain dynamics (dV), and (indirectly) germline:germline contacts between CDR2 and the MHC -helices (d) [24,44,49,[59][60][61].…”

Section: Discussionmentioning

confidence: 99%

CDR3 binding chemistry controls TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

Js¹

2019

Preprint

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The mechanism which 'adapts' the T-cell antigen receptor (TCR) repertoire within a given major histocompatibility complex (MHC; HLA, in humans) genotype is essential for protection against rapidly dividing pathogens. Historically attributed to relative affinity, genetically vast TCRs are surprisingly "focused" towards a micromolar affinity for their respective pHLA ligands. Thus, the somatic diversity of the TCR with respect to MHC restriction, and (ultimately) to pathogens, remains enigmatic. Here, we derive a triple integral equation (from fixed geometry) for any given V-domain in TCR bound to pMHC. We examined solved complexes involving HLA-DR and HLA-DQ, where all the available structures are still reasonably analysed. Certain V-beta domains displayed "rare" geometry within this panelspecifying a very low ("highly-restricted") rotational probability/volumetric density (dV). Remarkably, hydrogen (H)-bond charge-relays spanning CDR3-beta, the peptide, and polymorphic MHC distinguished these structures from the others; suggesting that CDR3 binding chemistry dictates CDR2 'scanning' on the respective MHC-II alpha-helix. Taken together, this analysis (n = 38 V-domains) supports a novel geometric theory for MHC restriction-one not constrained by a thymus "optimized" TCR-affinity.

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Integrating Experiment and Theory to Understand TCR-pMHC Dynamics

Cited by 26 publications

References 131 publications

The Role of Conformational Dynamics in abacavir-Induced Hypersensitivity Syndrome

The Role of Conformational Dynamics in abacavir-Induced Hypersensitivity Syndrome

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection

CDR3 binding chemistry controls TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

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