Purification, Crystallization and Crystallographic Analysis of HLA-B*15:02 Complexed with an Endogenous Peptide

Resumo

The drug hypersensitivity syndrome (DHS) caused by immune response to the drug is one of the major categories of adverse drug reactions. It has been demonstrated that DHSs involve an interaction of specific major histocompatibility complex (MHC, also known as the HLA in humans) molecules, T-cell receptors, and drugs. It has been also shown that some of the most common DHS diseases are strongly associated with certain HLA allotypes. Crystallographic studies are needed to elucidate the structural bases of HLA-drug associations and their biological roles in diverse DHSs. Carbamazepine (CBZ) is an anticonvulsant and mood stabilizing drug and it could cause serious hypersensitivity reactions. A nearly 100% association of HLA-B*15:02 with CBZ-induced DHS suggests that the HLA-B*15:02 is a central participant in the pathogenesis of the disease. Here, recombinant HLA-B*15:02 was co-crystallized with an endogenous peptide. Crystals belong to the trigonal space group P1, with the unit-cell parameters a = 71.89, b = 75.81, c = 88.47 Å, α = 97.28°, β = 90.43°, γ = 92.25°. Preliminary analysis indicates that the asymmetric unit contains four molecules of HLA-B*15:02 complexed with peptide and has a solvent content of about 49%.