人碳酸酐酶II与乙酰唑胺复合物的高分辨率结构为抑制剂药物设计提供了见解。
High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design.
作者信息
Sippel Katherine H, Robbins Arthur H, Domsic John, Genis Caroli, Agbandje-McKenna Mavis, McKenna Robert
机构信息
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
出版信息
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2009 Oct 1;65(Pt 10):992-5. doi: 10.1107/S1744309109036665. Epub 2009 Sep 25.
Abstract
The crystal structure of human carbonic anhydrase II (CA II) complexed with the inhibitor acetazolamide (AZM) has been determined at 1.1 A resolution and refined to an R(cryst) of 11.2% and an R(free) of 14.7%. As observed in previous CA II-inhibitor complexes, AZM binds directly to the zinc and makes several key interactions with active-site residues. The high-resolution data also showed a glycerol molecule adjacent to the AZM in the active site and two additional AZMs that are adventitiously bound on the surface of the enzyme. The co-binding of AZM and glycerol in the active site demonstrate that given an appropriate ring orientation and substituents, an isozyme-specific CA inhibitor may be developed.
摘要
已确定与抑制剂乙酰唑胺（AZM）复合的人碳酸酐酶II（CA II）的晶体结构，分辨率为1.1埃，精修后R(cryst)为11.2%，R(free)为14.7%。正如在先前的CA II-抑制剂复合物中所观察到的，AZM直接与锌结合，并与活性位点残基形成几个关键相互作用。高分辨率数据还显示在活性位点中有一个甘油分子与AZM相邻，以及另外两个偶然结合在酶表面的AZM。AZM和甘油在活性位点的共同结合表明，给定合适的环取向和取代基，可能开发出一种同工酶特异性的CA抑制剂。
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