Wilson D K, Rudolph F B, Quiocho F A
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030.
Science. 1991 May 31;252(5010):1278-84. doi: 10.1126/science.1925539.
The crystal structure of a murine adenosine deaminase complexed with 6-hydroxyl-1,6-dihydropurine ribonucleoside, a nearly ideal transition-state analog, has been determined and refined at 2.4 angstrom resolution. The structure is folded as an eight-stranded parallel alpha/beta barrel with a deep pocket at the beta-barrel COOH-terminal end wherein the inhibitor and a zinc are bound and completely sequestered. The presence of the zinc cofactor and the precise structure of the bound analog were not previously known. The 6R isomer of the analog is very tightly held in place by the coordination of the 6-hydroxyl to the zinc and the formation of nine hydrogen bonds. On the basis of the structure of the complex a stereoselective addition-elimination or SN2 mechanism of the enzyme is proposed with the zinc atom and the Glu and Asp residues playing key roles. A molecular explanation of a hereditary disease caused by several point mutations of an enzyme is also presented.
已确定并以2.4埃分辨率精修了与6-羟基-1,6-二氢嘌呤核糖核苷（一种近乎理想的过渡态类似物）复合的小鼠腺苷脱氨酶的晶体结构。该结构折叠成一个八链平行的α/β桶状结构，在β桶状结构的COOH末端有一个深口袋，抑制剂和一个锌结合在其中并被完全隔离。此前并不知道锌辅因子的存在以及结合类似物的精确结构。该类似物的6R异构体通过6-羟基与锌的配位以及九个氢键的形成而非常紧密地固定在位。基于复合物的结构，提出了该酶的立体选择性加成-消除或SN2机制，其中锌原子以及Glu和Asp残基起关键作用。还给出了由一种酶的几个点突变引起的遗传性疾病的分子解释。
