Department of Dermatology, Showa University School of Medicine, Tokyo, Japan.
Department of Analytical and Physical Chemistry, Showa University School of Pharmacy, Tokyo, Japan.
J Dermatol Sci. 2017 Dec;88(3):320-329. doi: 10.1016/j.jdermsci.2017.08.007. Epub 2017 Aug 24.
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.
To investigate why HLA-B*13:01 is responsible for DHS from a structural point of view.
First, we used homology modeling to derive the three-dimensional structures of HLA-B13:01 (associated with DHS) and HLA-B13:02 (not so associated despite strong sequence identity [99%] with HLA-B13:01). 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-B13:01 and 13:02.
We found a crucial structural difference between HLA-B13:01 and 13:02 in the F-pocket of the antigen-binding site. As Trp95 in the α-domain of HLA-B13:02 is replaced with the less bulky Ile95 in HLA-B13:01, we found an additional well-defined sub-pocket within the antigen-binding site of HLA-B13:01. All three representative docking poses of dapsone against the antigen-binding site of HLA-B13:01 used this unique sub-pocket, indicating its suitability for binding dapsone. However, HLA-B13:02 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-B13:01 would be much greater than that for HLA-B13:02.
Our computational results suggest that dapsone would fit within the structure of the antigen-recognition site of HLA-B13:01. This may change the self-peptides that bind to HLA-B13:01, explaining why HLA-B*13:01 is a marker of DHS susceptibility.
氨苯砜（4,4'-二氨基二苯砜）已被广泛用于治疗麻风病等感染。氨苯砜过敏综合征（DHS）是一种主要的副作用，在接受氨苯砜治疗的患者中发生率为 0.5-3.6%，死亡率约为 10%。最近，人类白细胞抗原（HLA）-B*13:01 被确定为 DHS 易感性的标志物。
从结构角度探讨为什么 HLA-B*13:01 与 DHS 有关。
首先，我们使用同源建模推导出与 DHS 相关的 HLA-B13:01（与 DHS 相关）和 HLA-B13:02（与 DHS 相关，尽管与 HLA-B13:01 具有很强的序列同一性[99%]）的三维结构。接下来，我们使用分子对接、分子动力学模拟和分子力学泊松-玻尔兹曼表面面积方法，研究了氨苯砜与 HLA-B13:01 和 13:02 的相互作用。
我们发现 HLA-B13:01 和 13:02 在抗原结合部位的 F 口袋之间存在一个关键的结构差异。由于 HLA-B13:02 的α-结构域中的色氨酸 95 被体积较小的异亮氨酸 95 取代，我们在 HLA-B13:01 的抗原结合部位内发现了一个额外的明确亚口袋。氨苯砜与 HLA-B13:01 抗原结合部位的所有三个代表性对接构象都使用了这个独特的亚口袋，表明它适合结合氨苯砜。然而，HLA-B13:02 似乎不具有适合结合氨苯砜的结合口袋。最后，结合分子动力学模拟和分子力学泊松-玻尔兹曼表面面积方法的结合自由能计算表明，氨苯砜与 HLA-B13:01 的结合亲和力将远大于与 HLA-B*13:02 的结合亲和力。
我们的计算结果表明，氨苯砜将适合 HLA-B13:01 的抗原识别部位结构。这可能会改变与 HLA-B13:01 结合的自身肽，解释了为什么 HLA-B*13:01 是 DHS 易感性的标志物。
