Asymmetry in catalysis by Thermotoga maritima membrane-bound pyrophosphatase demonstrated by a nonphosphorus allosteric inhibitor

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Vidilaseris , K , Kiriazis , A , Turku , A , Khattab , A A S , Johansson , N G , Leino , T O , Kiuru , P S , Boije af Gennäs , P G , Meri , S K , Yli-Kauhaluoma , J T , Xhaard , H G M & Goldman , A 2019 , ' Asymmetry in catalysis by Thermotoga maritima membrane-bound pyrophosphatase demonstrated by a nonphosphorus allosteric inhibitor ' , Science Advances , vol. 5 , no. 5 , 7574 . https://doi.org/10.1126/sciadv.aav7574

Title: Asymmetry in catalysis by Thermotoga maritima membrane-bound pyrophosphatase demonstrated by a nonphosphorus allosteric inhibitor
Author: Vidilaseris, Keni; Kiriazis, Alexandros; Turku, Ainoleena; Khattab, Ayman Abdelnaby Shaaban; Johansson, Niklas G; Leino, Teppo Olavi; Kiuru, Paula Sinikka; Boije af Gennäs, Per Gustav; Meri, Seppo Kalevi; Yli-Kauhaluoma, Jari Tapani; Xhaard, Henri Guillaume Michel; Goldman, Adrian
Contributor organization: Molecular and Integrative Biosciences Research Programme
Pharmaceutical Design and Discovery group
Division of Pharmaceutical Chemistry and Technology
Faculty of Pharmacy
Drug Research Program
Department of Bacteriology and Immunology
Research Programs Unit
Medicum
HUSLAB
Seppo Meri / Principal Investigator
Jari Yli-Kauhaluoma / Principal Investigator
Computational Adme
Henri Xhaard / Principal Investigator
Division of Pharmaceutical Biosciences
Biochemistry and Biotechnology
Date: 2019-05-22
Language: eng
Number of pages: 12
Belongs to series: Science Advances
ISSN: 2375-2548
DOI: https://doi.org/10.1126/sciadv.aav7574
URI: http://hdl.handle.net/10138/303494
Abstract: Membrane-bound pyrophosphatases are homodimeric integral membrane proteins that hydrolyze pyrophosphate into orthophosphates, coupled to the active transport of protons or sodium ions across membranes. They are important in the life cycle of bacteria, archaea, plants, and parasitic protists, but no homologous proteins exist in vertebrates, making them a promising drug target. Here, we report the first nonphosphorus allosteric inhibitor of the thermophilic bacterium Thermotoga maritima membrane-bound pyrophosphatase and its bound structure together with the substrate analog imidodiphosphate. The unit cell contains two protein homodimers, each binding a single inhibitor dimer near the exit channel, creating a hydrophobic clamp that inhibits the movement of beta-strand 1-2 during pumping, and thus prevents the hydrophobic gate from opening. This asymmetry of inhibitor binding with respect to each homodimer provides the first clear structural demonstration of asymmetry in the catalytic cycle of membrane-bound pyrophosphatases.
Subject: ACIDOCALCISOMES
BISPHOSPHONATES
EVOLUTIONARY CONSERVATION
INORGANIC PYROPHOSPHATASE
LEISHMANIA-DONOVANI
LOCALIZATION
PLASMODIUM-FALCIPARUM
TOXOPLASMA-GONDII
TRYPANOSOMA-BRUCEI
VACUOLAR-H+-PYROPHOSPHATASE
317 Pharmacy
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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