Biology subjects

Borg, N. A.

Publications and source records attributed to Borg, N. A..

2 recordsLinked to original sources

bioRxiv2017

The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome

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. Abacavirs 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.

immunology↗

bioRxiv2017

Previously Hidden Dynamics at the TCR-pMHC Interface Revealed

A structural characterization of the interaction between T cell receptors (TCR) and cognate peptide-MHC (pMHC) is central to understanding adaptive T cell mediated immunity. X-ray crystallography, although the source of much structural data, traditionally provides only a static snapshot of the protein. Given the emerging evidence for the important role of conformational dynamics in protein function, we interrogated 309 crystallographic structures of pMHC complexes using ensemble refinement, a technique that can extract dynamic information from the X-ray data. We found that in a large number of systems ensemble methods were able to uncover previously hidden evidence of significant conformational plasticity, thereby revealing additional information that can build upon and significantly enhance functional interpretations that are based on a single static structure. Notable examples include the interpretation of differences in the disease association of HLA subtypes, the relationship between peptide prominence and TCR recognition, the role of conformational flexibility in vaccine design, and discriminating between induced fit and conformational selection models of TCR binding. We show that the currently widespread practise of analyzing pMHC interactions via the study of a single crystallographic structure does not make use of pertinent and easily accessible information from X-ray data concerning alternative protein conformations. This new analysis therefore not only highlights the capacity for ensemble methods to significantly enrich the interpretation of decades of structural data, but also provides previously missing information concerning the dynamics of existing characterized TCR-pMHC interactions.

immunology↗