探索的GM1受体结合部位的heat-labile肠毒素和霍乱毒素phenyl-ring-containing半乳糖衍生品。
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风扇E,梅里特EA,张Z,皮肯斯JC,罗奇C,安米,假日工作组
探索的GM1受体结合部位的heat-labile肠毒素和霍乱毒素phenyl-ring-containing半乳糖衍生品。
Acta Crystallogr D Crystallogr杂志。2001年2月,57 (Pt 2): 201 - 12所示。
- PubMed ID
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11173465 (在PubMed]
- 文摘
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霍乱毒素(CT)和heat-labile密切相关的大肠杆菌肠毒素(LT)负责全球无数例腹泻,导致相当大的发病率和死亡率。这些heterohexameric AB的B亚基(5)毒素形成pentameric安排负责绑定的受体GM1目标主机的上皮细胞。阻止这些B pentamer-receptor交互形式治疗干预的途径。这里,潜在receptor-blocking化合物的结构特征描述是基于先前确定抑制剂m-nitrophenyl-alpha-D-galactoside (MNPG)。CTB-MNPG复杂的结构确认这种抑制剂的绑定模式是相同的两个同源毒素CT和LT和特征是一个糖基连杆几何位移导致的命令酰胺基附近的水分子的O1-substituent Gly33 MNPG。这个糖基几何不保持在缺乏取代基取代水,如图所示,一个复杂的LTB p-aminophenyl-alpha-D-galactoside (PAPG)。新化合物合成研究的可行性保持有利的绑定交互展示通过MNPG而获得增加亲和力的疏水性取代基补充两种受体结合的疏水区域的网站。复合物的结构表征的LTB两种化合物,3-benzylaminocarbonylphenyl-alpha-D-galactoside (BAPG)和2-phenethyl-7 - (2 3-dihydrophthalazine-1 4-dione) -alpha-D-galactoside (PEPG),演示了一个部分的成功这一目标。两种化合物表现出的混合绑定模式,其中一些可能影响当地的包装环境在多个结晶学独立的结合位点。终端BAPG associates的苯基环Tyr12的苯基或Lys34形成的疏水性补丁和Ile58。 The latter interaction is also made by the terminal phenyl substituent of PEPG, despite a larger ring system linking the galactose moiety to the terminal phenyl. However, neither BAPG nor PEPG displaces the intended target water molecule. Both of the designed compounds exhibit increased affinity relative to the galactose and to PAPG notwithstanding the failure to displace a bound water, confirming that additional favorable hydrophobic interactions can be gained by extending the starting inhibitor by a hydrophobic tail. The insight gained from these structures should allow the design of additional candidate inhibitors that retain both the glycosyl geometry and water displacement exhibited by MNPG and the favorable hydrophobic interactions exhibited by BAPG and PEPG.