Structural Basis for Antibody Catalysis of a Disfavored Ring Closure Reaction

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• 作者：Karl Gruber ; Bin Zhou ; Kendall N. Houk ; Richard A. Lerner ; Charles G. Shevlin ; and Ian A. Wilson
• 刊名：Biochemistry
• 出版年：1999
• 出版时间：June 1, 1999
• 年：1999
• 卷：38
• 期：22
• 页码：7062 - 7074
• 全文大小：285K
• 年卷期：v.38,no.22(June 1, 1999)
• ISSN：1520-4995

文摘

The catalysis of disfavored chemical reactions, especially those with no known natural enzymecounterparts, is one of the most promising achievements of catalytic antibody research. Antibodies 5C8,14B9, 17F6, and 26D9, elicited by two different transition-state analogues, catalyze disfavored endo-tetcyclization reactions of trans-epoxy alcohols, in formal violation of Baldwin's rules for ring closure.Thus far, neither chemical nor enzyme catalysis has been capable of emulating the extraordinary activityand specificity of these antibodies. X-ray structures of two complexes of Fab 5C8 with the original haptenand with an inhibitor have been determined to 2.0 Å resolution. The Fab structure has an active site thatcontains a putative catalytic diad, consisting of Asp^H95 and His^L89, capable of general acid/base catalysis.The stabilization of a positive charge that develops along the reaction coordinate appears to be an importantfactor for rate enhancement and for directing the reaction along the otherwise disfavored pathway. Sequenceanalysis of the four catalytic antibodies, as well as four inactive antibodies that strongly bind the transition-state analogues, suggests a conserved catalytic mechanism. The occurrence of the putative base His^L89 inall active antibodies, its absence in three out of the four analyzed inactive antibodies, and the rarity of ahistidine at this position in immunoglobulins support an important catalytic role for this residue.