与“双叉”抑制剂复合的人碳酸酐酶I和II的超高分辨率晶体结构揭示了高亲和力的分子基础。
Ultrahigh resolution crystal structures of human carbonic anhydrases I and II complexed with "two-prong" inhibitors reveal the molecular basis of high affinity.
作者信息
Jude Kevin M, Banerjee Abir L, Haldar Manas K, Manokaran Sumathra, Roy Bidhan, Mallik Sanku, Srivastava D K, Christianson David W
机构信息
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
出版信息
J Am Chem Soc. 2006 Mar 8;128(9):3011-8. doi: 10.1021/ja057257n.
Abstract
The atomic-resolution crystal structures of human carbonic anhydrases I and II complexed with "two-prong" inhibitors are reported. Each inhibitor contains a benzenesulfonamide prong and a cupric iminodiacetate (IDA-Cu(2+)) prong separated by linkers of different lengths and compositions. The ionized NH(-) group of each benzenesulfonamide coordinates to the active site Zn(2+) ion; the IDA-Cu(2+) prong of the tightest-binding inhibitor, BR30, binds to H64 of CAII and H200 of CAI. This work provides the first evidence verifying the structural basis of nanomolar affinity measured for two-prong inhibitors targeting the carbonic anhydrases.
摘要
报道了与“双叉”抑制剂复合的人碳酸酐酶I和II的原子分辨率晶体结构。每种抑制剂都包含一个苯磺酰胺叉和一个由不同长度和组成的连接子隔开的亚氨基二乙酸铜（IDA-Cu(2+)）叉。每个苯磺酰胺的离子化NH(-)基团与活性位点的Zn(2+)离子配位；结合最紧密的抑制剂BR30的IDA-Cu(2+)叉与CAII的H64和CAI的H200结合。这项工作提供了首个证据，验证了针对碳酸酐酶的双叉抑制剂纳摩尔亲和力的结构基础。
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