Insights into the mechanism of membrane pyrophosphatases by combining experiment and computer simulation

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Shah , N R , Wilkinson , C , Harborne , S P D , Turku , A , Li , K-M , Sun , Y-J , Harris , S & Goldman , A 2017 , ' Insights into the mechanism of membrane pyrophosphatases by combining experiment and computer simulation ' , Structural dynamics , vol. 4 , no. 3 , 032105 . https://doi.org/10.1063/1.4978038

Title: Insights into the mechanism of membrane pyrophosphatases by combining experiment and computer simulation
Author: Shah, Nita R.; Wilkinson, Craig; Harborne, Steven P. D.; Turku, Ainoleena; Li, Kun-Mou; Sun, Yuh-Ju; Harris, Sarah; Goldman, Adrian
Contributor organization: University of Helsinki
Faculty of Pharmacy
Division of Pharmaceutical Chemistry and Technology
Biosciences
Biochemistry and Biotechnology
Date: 2017-05
Language: eng
Number of pages: 12
Belongs to series: Structural dynamics
ISSN: 2329-7778
DOI: https://doi.org/10.1063/1.4978038
URI: http://hdl.handle.net/10138/190456
Abstract: Membrane-integral pyrophosphatases (mPPases) couple the hydrolysis of pyrophosphate (PPi) to the pumping of Na+, H+, or both these ions across a membrane. Recently solved structures of the Na+-pumping Thermotoga maritima mPPase (TmPPase) and H+-pumping Vigna radiata mPPase revealed the basis of ion selectivity between these enzymes and provided evidence for the mechanisms of substrate hydrolysis and ion-pumping. Our atomistic molecular dynamics (MD) simulations of TmPPase demonstrate that loop 5-6 is mobile in the absence of the substrate or substrate-analogue bound to the active site, explaining the lack of electron density for this loop in resting state structures. Furthermore, creating an apo model of TmPPase by removing ligands from the TmPPase: IDP: Na structure in MD simulations resulted in increased dynamics in loop 5-6, which results in this loop moving to uncover the active site, suggesting that interactions between loop 5-6 and the imidodiphosphate and its associated Mg2+ are important for holding a loop-closed conformation. We also provide further evidence for the transport-before-hydrolysis mechanism by showing that the non-hydrolyzable substrate analogue, methylene diphosphonate, induces low levels of proton pumping by VrPPase. (C) 2017 Author(s).
Subject: H+-PYROPHOSPHATASE
PUMPING PYROPHOSPHATASE
INORGANIC PYROPHOSPHATE
MOLECULAR-DYNAMICS
FORCE-FIELD
ACIDOCALCISOMES
NA+
OVEREXPRESSION
CONSERVATION
STRESS
116 Chemical sciences
317 Pharmacy
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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