ROUTES TO CATALYSIS - STRUCTURE OF A CATALYTIC ANTIBODY AND COMPARISON WITH ITS NATURAL COUNTERPART
ROUTES TO CATALYSIS - STRUCTURE OF A CATALYTIC ANTIBODY AND COMPARISON WITH ITS NATURAL COUNTERPART
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DOI：
10.1126/science.8303271
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发表时间：
1994-02-04
期刊：
影响因子：
56.9
通讯作者：
WILSON, IA
中科院分区：
文献类型：
--
作者：
HAYNES, MR;STURA, EA;WILSON, IA
作为具有过渡态类似物的复合物，具有分支酸盐还原活性的催化抗体（1F 7）的三维结构已被确定为3.0埃分辨率。结构数据表明，抗体稳定相同的构象限制的周环过渡态中发生的非催化反应。结合位点和过渡态类似物之间的整体形状和电荷互补性决定了正确底物对映异构体以适合于反应的构象优先结合。与分支酸脱氢酶的结构比较表明，这两种蛋白质所采用的催化机制之间具有总体相似性。可用于限制过渡态旋转自由度的特定相互作用数量的差异，以及缺乏可能稳定这种高度极化亚稳态物质中电荷分离的多种静电相互作用，可能是观察到的低10（4）倍的原因相对于催化该反应的天然酶，抗体的活性。1F 7 Fab ′-半抗原复合物的结构证实了抗体催化剂的性质忠实地反映了过渡态类似物的设计。
The three-dimensional structure of a catalytic antibody (1F7) with chorismate mutase activity has been determined to 3.0 angstrom resolution as a complex with a transition state analog. The structural data suggest that the antibody stabilizes the same conformationally restricted pericyclic transition state as occurs in the uncatalyzed reaction. Overall shape and charge complementarity between the combining site and the transition state analog dictate preferential binding of the correct substrate enantiomer in a conformation appropriate for reaction. Comparison with the structure of a chorismate mutase enzyme indicates an overall similarity between the catalytic mechanism employed by the two proteins. Differences in the number of specific interactions available for restricting the rotational degrees of freedom in the transition state, and the lack of multiple electrostatic interactions that might stabilize charge separation in this highly polarized metastable species, are likely to account for the observed 10(4) times lower activity of the antibody relative to that of the natural enzymes that catalyze this reaction. The structure of the 1F7 Fab'-hapten complex provides confirmation that the properties of an antibody catalyst faithfully reflect the design of the transition state analog.