尾-Amyloid and Neprilysin Computational Studies Identify Critical Residues Implicated in Binding Specificity

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• 作者：Darrick Pope ; Jeffry D. Madura ; Michael Cascio
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2014
• 出版时间：April 28, 2014
• 年：2014
• 卷：54
• 期：4
• 页码：1157-1165
• 全文大小：389K
• 年卷期：v.54,no.4(April 28, 2014)
• ISSN：1549-960X

文摘

The zinc metalloprotease neprilysin (NEP) promiscuously degrades small bioactive peptides. NEP is among a select group of metalloenzymes that degrade the amyloid beta-peptide (A尾) in vivo and in situ. Since accumulation of neurotoxic A尾 aggregates in the brain appears to be a causative agent in the pathophysiology of Alzheimer鈥檚 disease (AD), increased clearance of A尾 resulting from overexpression of NEP exhibits therapeutic potential for AD. However, higher NEP peptidase activity may be harmful without an increased specificity for A尾 over other competing substrates. Crystal structures of NEP鈥搃nhibitor complexes and their characterization have highlighted potential amino acid interactions involved in substrate binding and are used as templates to guide our methodology in docking A尾 in NEP. Results from protein鈥搇igand docking calculations predict S2鈥?subsite residues Arg 102 and Arg 110 of NEP participate in specific interactions with A尾. These interactions provide insight into developing NEP specificity for A尾.