Hideaki Watanabe1, Yurie Watanabe2, Yasuya Tashiro3, Taisei Mushiroda4, Takeshi Ozeki4, Hideo Hashizume5, Hirohiko Sueki3, Toshinori Yamamoto6, Naoko Utsunomiya-Tate7, Hiroaki Gouda8, Yoshio Kusakabe9. 1. Department of Dermatology, Showa University School of Medicine, Tokyo, Japan. Electronic address: hwatanabe@med.showa-u.ac.jp. 2. Department of Analytical and Physical Chemistry, Showa University School of Pharmacy, Tokyo, Japan. 3. Department of Dermatology, Showa University School of Medicine, Tokyo, Japan. 4. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 5. Department of Dermatology, Shimada Municipal Hospital, Shizuoka, Japan. 6. Showa University Medical Foundation, Showa University School of Pharmacy, Tokyo, Japan. 7. Laboratory of Chemistry, Faculty of Pharma Sciences, Teikyo University, Tokyo, Japan. 8. Department of Analytical and Physical Chemistry, Showa University School of Pharmacy, Tokyo, Japan. Electronic address: godah@pharm.showa-u.ac.jp. 9. Department of Analytical and Physical Chemistry, Showa University School of Pharmacy, Tokyo, Japan; Laboratory of Chemistry, Faculty of Pharma Sciences, Teikyo University, Tokyo, Japan.
Abstract
BACKGROUND: Dapsone (4,4'-diaminodiphenylsulfone) has been widely used for the treatment of infections such as leprosy. Dapsone hypersensitivity syndrome (DHS) is a major side effect, developing in 0.5-3.6% of patients treated with dapsone, and its mortality rate is ∼10%. Recently, human leukocyte antigen (HLA)-B*13:01 was identified as a marker of susceptibility to DHS. OBJECTIVES: To investigate why HLA-B*13:01 is responsible for DHS from a structural point of view. METHODS: First, we used homology modeling to derive the three-dimensional structures of HLA-B*13:01 (associated with DHS) and HLA-B*13:02 (not so associated despite strong sequence identity [99%] with HLA-B*13:01). Next, we used molecular docking, molecular dynamic simulations, and the molecular mechanics Poisson-Boltzman surface area method, to investigate the interactions of dapsone with HLA-B*13:01 and 13:02. RESULTS: We found a crucial structural difference between HLA-B*13:01 and 13:02 in the F-pocket of the antigen-binding site. As Trp95 in the α-domain of HLA-B*13:02 is replaced with the less bulky Ile95 in HLA-B*13:01, we found an additional well-defined sub-pocket within the antigen-binding site of HLA-B*13:01. All three representative docking poses of dapsone against the antigen-binding site of HLA-B*13:01 used this unique sub-pocket, indicating its suitability for binding dapsone. However, HLA-B*13:02 does not seem to possess a binding pocket suitable for binding dapsone. Finally, a binding free energy calculation combined with a molecular dynamics simulation and the molecular mechanics Poisson-Boltzman surface area method indicated that the binding affinity of dapsone for HLA-B*13:01 would be much greater than that for HLA-B*13:02. CONCLUSIONS: Our computational results suggest that dapsone would fit within the structure of the antigen-recognition site of HLA-B*13:01. This may change the self-peptides that bind to HLA-B*13:01, explaining why HLA-B*13:01 is a marker of DHS susceptibility.
BACKGROUND:Dapsone (4,4'-diaminodiphenylsulfone) has been widely used for the treatment of infections such as leprosy. Dapsonehypersensitivity syndrome (DHS) is a major side effect, developing in 0.5-3.6% of patients treated with dapsone, and its mortality rate is ∼10%. Recently, humanleukocyte antigen (HLA)-B*13:01 was identified as a marker of susceptibility to DHS. OBJECTIVES: To investigate why HLA-B*13:01 is responsible for DHS from a structural point of view. METHODS: First, we used homology modeling to derive the three-dimensional structures of HLA-B*13:01 (associated with DHS) and HLA-B*13:02 (not so associated despite strong sequence identity [99%] with HLA-B*13:01). Next, we used molecular docking, molecular dynamic simulations, and the molecular mechanics Poisson-Boltzman surface area method, to investigate the interactions of dapsone with HLA-B*13:01 and 13:02. RESULTS: We found a crucial structural difference between HLA-B*13:01 and 13:02 in the F-pocket of the antigen-binding site. As Trp95 in the α-domain of HLA-B*13:02 is replaced with the less bulky Ile95 in HLA-B*13:01, we found an additional well-defined sub-pocket within the antigen-binding site of HLA-B*13:01. All three representative docking poses of dapsone against the antigen-binding site of HLA-B*13:01 used this unique sub-pocket, indicating its suitability for binding dapsone. However, HLA-B*13:02 does not seem to possess a binding pocket suitable for binding dapsone. Finally, a binding free energy calculation combined with a molecular dynamics simulation and the molecular mechanics Poisson-Boltzman surface area method indicated that the binding affinity of dapsone for HLA-B*13:01 would be much greater than that for HLA-B*13:02. CONCLUSIONS: Our computational results suggest that dapsone would fit within the structure of the antigen-recognition site of HLA-B*13:01. This may change the self-peptides that bind to HLA-B*13:01, explaining why HLA-B*13:01 is a marker of DHS susceptibility.