Kontopidis George, Taylor Paul, Walkinshaw Malcolm D
Structural Biochemistry Group, Department of Biochemistry, The University of Edinburgh, Michael Swann Building, King's Buildings, Edinburgh EH9 3JR, Scotland.
Acta Crystallogr D Biol Crystallogr. 2004 Mar;60(Pt 3):479-85. doi: 10.1107/S0907444904000174. Epub 2004 Feb 25.
Piperidine ligands are described that provide the first examples of non-peptidic ligand structures for the cyclophilin family of proteins. Crystal structures of two ligand complexes are compared with the unliganded protein and show ligand-induced changes in side-chain conformation and water binding. A peptidylprolyl cis-trans-isomerase assay showed the dissociation constants of the two ligands to be 320 and 25 mM. This study also provides the first published data for both enzymatic activity and three-dimensional structure for any protein-ligand complex that binds with a high-millimolar dissociation constant. The structures may be of relevance in the field of drug design, as they suggest starting points for the design of larger tighter-binding analogues.
本文描述了哌啶配体，它们是亲环蛋白家族蛋白质非肽配体结构的首个实例。将两种配体复合物的晶体结构与未结合配体的蛋白质进行比较，结果表明配体诱导了侧链构象和水结合的变化。肽基脯氨酰顺反异构酶分析显示，这两种配体的解离常数分别为320 mM和25 mM。该研究还首次公布了任何以高毫摩尔解离常数结合的蛋白质-配体复合物的酶活性和三维结构数据。这些结构可能与药物设计领域相关，因为它们为设计更大的紧密结合类似物提供了起点。
