ATOMIC-STRUCTURE OF ADENOSINE-DEAMINASE COMPLEXED WITH A TRANSITION-STATE ANALOG - UNDERSTANDING CATALYSIS AND IMMUNODEFICIENCY MUTATIONS
ATOMIC-STRUCTURE OF ADENOSINE-DEAMINASE COMPLEXED WITH A TRANSITION-STATE ANALOG - UNDERSTANDING CATALYSIS AND IMMUNODEFICIENCY MUTATIONS
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DOI：
10.1126/science.1925539
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发表时间：
1991-05-31
期刊：
影响因子：
56.9
通讯作者：
QUIOCHO, FA
中科院分区：
文献类型：
--
作者：
WILSON, DK;RUDOLPH, FB;QUIOCHO, FA
与6-羟基-1,6-二氢嘌呤核糖核苷（一种接近理想的过渡态类似物）相络合的鼠腺苷脱氨酶的晶体结构已在2.4 Angstrom分辨率下进行了确定和完善。 该结构被折叠成八链平行的α/β-桶，在β-桶COOH末端的深口袋中，抑制剂和锌是结合并完全隔离的。 以前不知道锌辅因子的存在和结合类似物的精确结构。 通过6-羟基对锌的配位和九种氢键的形成，模拟的6R异构体非常紧密地固定在适当的位置。 根据络合物的结构，提出了酶的立体选择性加法 - 酶或s（n）2机理，该机制是用锌原子，GLU和ASP残基扮演关键作用的。 还提出了对酶几个点突变引起的遗传疾病的分子解释。
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 S(N)2 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.