Golinelli-Pimpaneau B, Gigant B, Bizebard T, Navaza J, Saludjian P, Zemel R, Tawfik D S, Eshhar Z, Green B S, Knossow M
Laboratoire de Biologie Structurale, UMR 9920 CNRS Université Paris Sud Bat 34, CNRS, Gif sur Yvette, France.
Structure. 1994 Mar 15;2(3):175-83. doi: 10.1016/s0969-2126(00)00019-8.
Antibodies with catalytic properties can be prepared by eliciting an antibody response against 'transition state analog' haptens. The specificity, rate and number of reaction cycles observed with these antibodies more closely resemble the properties of enzymes than any of the many other known enzyme-mimicking systems.
We have determined to 3 A resolution the first X-ray structure of a catalytic antibody Fab. This antibody catalyzes the hydrolysis of a p-nitrophenyl ester. In conjunction with binding studies in solution, this structure of the uncomplexed site suggests a model for transition state fixation where two tyrosines mimic the oxyanion binding hole of serine proteases. A comparison with the structures of known Fabs specific for low molecular weight haptens reveals that this catalytic antibody has an unusually long groove at its combining site.
Since transition state analogs contain elements of the desired product, product inhibition is a severe problem in antibody catalysis. The observation of a long groove at the combining site may relate to the ability of this catalytic antibody to achieve multiple cycles of reaction.
具有催化特性的抗体可通过引发针对“过渡态类似物”半抗原的抗体反应来制备。与众多其他已知的模拟酶系统相比，这些抗体所观察到的特异性、反应速率和反应循环次数更类似于酶的特性。
我们已将一种催化抗体Fab的首个X射线结构解析到3埃分辨率。该抗体催化对硝基苯酯的水解。结合溶液中的结合研究，未结合位点的这种结构提示了一种过渡态固定模型，其中两个酪氨酸模拟丝氨酸蛋白酶的氧负离子结合口袋。与针对低分子量半抗原的已知Fab结构进行比较发现，这种催化抗体在其结合位点有一条异常长的凹槽。
由于过渡态类似物包含所需产物的元素，产物抑制在抗体催化中是一个严重问题。在结合位点观察到的长凹槽可能与这种催化抗体实现多个反应循环的能力有关。
