Unexpected Binding Mode of the Sulfonamide Fluorophore 5-Dimethylamino-1-naphthalene Sulfonamide to Human Carbonic Anhydrase II
Unexpected Binding Mode of the Sulfonamide Fluorophore 5-Dimethylamino-1-naphthalene Sulfonamide to Human Carbonic Anhydrase II
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磺酰胺荧光团 5-二甲氨基-1-萘磺酰胺与人碳酸酐酶 II 的意外结合模式
DOI：
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发表时间：
1996
影响因子：
4.8
通讯作者：
D. Christianson
中科院分区：
文献类型：
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作者：
S. Nair;D. Elbaum;D. Christianson
用X-射线晶体学方法测定了人碳酸酐酶Ⅱ（CAII）与磺酰胺荧光团5-二甲氨基-1-萘磺酰胺（丹磺酰胺）复合物的三维结构，其分辨率为2.1 μ m。与其他CAII的芳基磺酰胺抑制剂不同，丹磺酰胺的萘基环结合在活性位点的疏水口袋中，使货车德瓦尔斯与瓦尔-121、Phe-131、瓦尔-143、Leu-198和Trp-209接触。有趣的是，需要Leu-198的构象变化来适应丹磺酰胺结合，这使对某些Leu-198变体测量的增强的丹磺酰胺亲和力合理化（Nair，S. K.，Krebs，J.F.，Christianson，D. W.，和Fierke，C. A.（1995）Biochemistry 34，3981-3989）。建模研究表明，第二种结合模式，其中稠合芳环旋转出疏水口袋，是空间上可行的。实验观察到的和建模的结合模式有新的线索，在设计的亲和CAII抑制剂的影响。最后，CAII-丹磺酰胺复合物的结构具有其开发锌生物传感器应用的影响，和可能的路线走向优化的荧光团的设计被认为是在此结构的基础上。
The three-dimensional structure of human carbonic anhydrase II (CAII) complexed with the sulfonamide fluorophore 5-dimethylamino-1-naphthalene sulfonamide (dansylamide) has been determined to 2.1-Å resolution by x-ray crystallographic methods. Unlike other arylsulfonamide inhibitors of CAII, the naphthyl ring of dansylamide binds in a hydrophobic pocket in the active site, making van der Waals contacts with Val-121, Phe-131, Val-143, Leu-198, and Trp-209. Interestingly, a conformational change of Leu-198 is required to accommodate dansylamide binding, which rationalizes the enhanced dansylamide affinity measured for certain Leu-198 variants (Nair, S. K., Krebs, J. F., Christianson, D. W., and Fierke, C. A. (1995) Biochemistry 34, 3981–3989). Modeling studies indicate that a second binding mode, in which the fused aromatic ring is rotated out of the hydrophobic pocket, is sterically feasible. Both experimentally observed and modeled binding modes have implications for new leads in the design of avid CAII inhibitors. Finally, the structure of the CAII-dansylamide complex has implications for its exploitation in zinc biosensor applications, and possible routes toward the optimization of fluorophore design are considered on the basis on this structure.