Protein Dynamics and Enzymatic Catalysis: Investigating the Peptidyl-Prolyl Cis-Trans Isomerization Activity of Cyclophilin A

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• 作者：Pratul K. Agarwal ; Al Geist ; and Andrey Gorin
• 刊名：Biochemistry
• 出版年：2004
• 出版时间：August 24, 2004
• 年：2004
• 卷：43
• 期：33
• 页码：10605 - 10618
• 全文大小：683K
• 年卷期：v.43,no.33(August 24, 2004)
• ISSN：1520-4995

文摘

A growing body of evidence suggests a connection between protein dynamics and enzymaticcatalysis. In this paper, we present a variety of computational studies designed to investigate the role ofprotein dynamics in the detailed mechanism of peptidyl-prolyl cis-trans isomerization catalyzed byhuman cyclophilin A. The results identify a network of protein vibrations, extending from surface regionsof the enzyme to the active site and coupled to substrate turnover. Indications are that this network mayhave a role in promoting catalysis. Crucial parts of this network are found to be conserved in 10 cyclophilinstructures from six different species. Experimental evidence for the existence of this network comes fromprevious NMR relaxation studies, where motions in several residues, forming parts of this network, weredetected only during substrate turnover. The high temperature factors (from X-ray crystal structures)associated with the network residues provide further evidence of these vibrations. Along with the knowledgeof enzyme structure, this type of network could provide new insights into enzymatic catalysis and theeffect of distant ligand binding on protein function. The procedure outlined in this paper is general andcan be applied to other enzymatic systems as well. This presents an interesting opportunity; collaborativeexperimental and theoretical investigations designed to characterize in detail the nature and function ofthis type of network could enhance the understanding of protein dynamics in enzymatic catalysis.