Limits...
The Possible Mechanism of Idiosyncratic Lapatinib-Induced Liver Injury in Patients Carrying Human Leukocyte Antigen-DRB1*07:01.

Hirasawa M, Hagihara K, Okudaira N, Izumi T - PLoS ONE (2015)

Bottom Line: Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01.Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove.This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.

View Article: PubMed Central - PubMed

Affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

ABSTRACT
Idiosyncratic lapatinib-induced liver injury has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01. In order to investigate its mechanism, interaction of lapatinib with HLA-DRB1*07:01 and its ligand peptide derived from tetanus toxoid, has been evaluated in vitro. Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01. Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove. These results indicate that lapatinib affects the ligand binding to HLA-DRB1*07:01 and idiosyncratic lapatinib-induced liver injury might be triggered by this mechanism. This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.

No MeSH data available.


Related in: MedlinePlus

Simulated parameters of lapatinib-bound HLA system.(a) Calculated Energies vs. time plot. (b) RMSF values of polypeptide backbone. The location of α and β chains and the residues that comprise the binding groove helices are indicated by the solid and dashed lines running just above the x-axis. Alpha chain (solid black), alpha chain helix (solid purple), beta chain (dashed black), beta chain helix (dashed purple). (c) RMSD values of polypeptide backbone vs. time plot. (d) The average distance between each Cα in the helix of the α chain and the closest Cα atom in the helix from the β chain.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4476721&req=5

pone.0130928.g004: Simulated parameters of lapatinib-bound HLA system.(a) Calculated Energies vs. time plot. (b) RMSF values of polypeptide backbone. The location of α and β chains and the residues that comprise the binding groove helices are indicated by the solid and dashed lines running just above the x-axis. Alpha chain (solid black), alpha chain helix (solid purple), beta chain (dashed black), beta chain helix (dashed purple). (c) RMSD values of polypeptide backbone vs. time plot. (d) The average distance between each Cα in the helix of the α chain and the closest Cα atom in the helix from the β chain.

Mentions: In all simulations, lapatinib remained bound in the binding groove throughout the entire simulation. Each of the energies of lapatinib-bound simulations stabilized within about 0.5 ns (Fig 4a), indicating that the simulations are energetically stable. The flexibility of HLA was very similar in all simulations (Fig 4b). The presence of a lapatinib decreased the overall flexibility of the DRB1*01:01 and DRB1*07:01 alleles compared to the apo simulations. Fig 4c shows that the RMSDs stabilize after 1 to 2 ns, indicating that the systems relaxed quickly. Fig 4d shows that the size of the binding groove changed differently in each system, suggesting that different lapatinib-allele combinations behave differently. In Fig 5 structural analyses of the lapatinib-bound simulations are presented in three panels. The primary differences in three simulations are the binding pose of lapatinib and the degree to which it alters the β chain helix.


The Possible Mechanism of Idiosyncratic Lapatinib-Induced Liver Injury in Patients Carrying Human Leukocyte Antigen-DRB1*07:01.

Hirasawa M, Hagihara K, Okudaira N, Izumi T - PLoS ONE (2015)

Simulated parameters of lapatinib-bound HLA system.(a) Calculated Energies vs. time plot. (b) RMSF values of polypeptide backbone. The location of α and β chains and the residues that comprise the binding groove helices are indicated by the solid and dashed lines running just above the x-axis. Alpha chain (solid black), alpha chain helix (solid purple), beta chain (dashed black), beta chain helix (dashed purple). (c) RMSD values of polypeptide backbone vs. time plot. (d) The average distance between each Cα in the helix of the α chain and the closest Cα atom in the helix from the β chain.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476721&req=5

pone.0130928.g004: Simulated parameters of lapatinib-bound HLA system.(a) Calculated Energies vs. time plot. (b) RMSF values of polypeptide backbone. The location of α and β chains and the residues that comprise the binding groove helices are indicated by the solid and dashed lines running just above the x-axis. Alpha chain (solid black), alpha chain helix (solid purple), beta chain (dashed black), beta chain helix (dashed purple). (c) RMSD values of polypeptide backbone vs. time plot. (d) The average distance between each Cα in the helix of the α chain and the closest Cα atom in the helix from the β chain.
Mentions: In all simulations, lapatinib remained bound in the binding groove throughout the entire simulation. Each of the energies of lapatinib-bound simulations stabilized within about 0.5 ns (Fig 4a), indicating that the simulations are energetically stable. The flexibility of HLA was very similar in all simulations (Fig 4b). The presence of a lapatinib decreased the overall flexibility of the DRB1*01:01 and DRB1*07:01 alleles compared to the apo simulations. Fig 4c shows that the RMSDs stabilize after 1 to 2 ns, indicating that the systems relaxed quickly. Fig 4d shows that the size of the binding groove changed differently in each system, suggesting that different lapatinib-allele combinations behave differently. In Fig 5 structural analyses of the lapatinib-bound simulations are presented in three panels. The primary differences in three simulations are the binding pose of lapatinib and the degree to which it alters the β chain helix.

Bottom Line: Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01.Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove.This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.

View Article: PubMed Central - PubMed

Affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.

ABSTRACT
Idiosyncratic lapatinib-induced liver injury has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01. In order to investigate its mechanism, interaction of lapatinib with HLA-DRB1*07:01 and its ligand peptide derived from tetanus toxoid, has been evaluated in vitro. Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01. Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the β chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove. These results indicate that lapatinib affects the ligand binding to HLA-DRB1*07:01 and idiosyncratic lapatinib-induced liver injury might be triggered by this mechanism. This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico.

No MeSH data available.


Related in: MedlinePlus