Immucillins in custom catalytic-site cavities

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• 作者：Andrew S. Murkin ; Keith Clinch ; Jennifer M. Mason ; Peter C. Tyler ; Vern L. Schramm
• 关键词：PNP ; Immucillin ; ImmH ; Mutant ; Binding ; Transition-state analogue
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 出版时间：15 November 2008
• 年：2008
• 卷：18
• 期：22
• 页码：5900-5903
• 全文大小：396 K

文摘

Neighboring-group participation in the reaction catalyzed by purine nucleoside phosphorylase involves a compression mode between the 5′- and 4′-ribosyl oxygens, facilitated by His257. The His257Gly mutant opens a space in the catalytic site. Hydrophobic 5′-substituted Immucillins are transition-state analogue inhibitors of this mutant enzyme. Dissociation constants as low as 2 pM are achieved, with K_m/K_d as high as 400,000,000.