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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.

Alkuperäiskielienglanti
Artikkeli7574
LehtiScience Advances
Vuosikerta5
Numero5
Sivumäärä12
ISSN2375-2548
DOI - pysyväislinkit
TilaJulkaistu - 22 toukokuuta 2019
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

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  • 317 Farmasia

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@article{d860f82af09544c1a25ff8ea62d64c14,
title = "Asymmetry in catalysis by Thermotoga maritima membrane-bound pyrophosphatase demonstrated by a nonphosphorus allosteric inhibitor",
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.",
keywords = "ACIDOCALCISOMES, BISPHOSPHONATES, EVOLUTIONARY CONSERVATION, INORGANIC PYROPHOSPHATASE, LEISHMANIA-DONOVANI, LOCALIZATION, PLASMODIUM-FALCIPARUM, TOXOPLASMA-GONDII, TRYPANOSOMA-BRUCEI, VACUOLAR-H+-PYROPHOSPHATASE, 317 Pharmacy",
author = "Keni Vidilaseris and Alexandros Kiriazis and Ainoleena Turku and Khattab, {Ayman Abdelnaby Shaaban} and Johansson, {Niklas G} and Leino, {Teppo Olavi} and Kiuru, {Paula Sinikka} and {Boije af Genn{\"a}s}, {Per Gustav} and Meri, {Seppo Kalevi} and Yli-Kauhaluoma, {Jari Tapani} and Xhaard, {Henri Guillaume Michel} and Adrian Goldman",
year = "2019",
month = "5",
day = "22",
doi = "10.1126/sciadv.aav7574",
language = "English",
volume = "5",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science (AAAS)",
number = "5",

}

TY - JOUR

T1 - Asymmetry in catalysis by Thermotoga maritima membrane-bound pyrophosphatase demonstrated by a nonphosphorus allosteric inhibitor

AU - Vidilaseris, Keni

AU - Kiriazis, Alexandros

AU - Turku, Ainoleena

AU - Khattab, Ayman Abdelnaby Shaaban

AU - Johansson, Niklas G

AU - Leino, Teppo Olavi

AU - Kiuru, Paula Sinikka

AU - Boije af Gennäs, Per Gustav

AU - Meri, Seppo Kalevi

AU - Yli-Kauhaluoma, Jari Tapani

AU - Xhaard, Henri Guillaume Michel

AU - Goldman, Adrian

PY - 2019/5/22

Y1 - 2019/5/22

N2 - 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.

AB - 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.

KW - ACIDOCALCISOMES

KW - BISPHOSPHONATES

KW - EVOLUTIONARY CONSERVATION

KW - INORGANIC PYROPHOSPHATASE

KW - LEISHMANIA-DONOVANI

KW - LOCALIZATION

KW - PLASMODIUM-FALCIPARUM

KW - TOXOPLASMA-GONDII

KW - TRYPANOSOMA-BRUCEI

KW - VACUOLAR-H+-PYROPHOSPHATASE

KW - 317 Pharmacy

U2 - 10.1126/sciadv.aav7574

DO - 10.1126/sciadv.aav7574

M3 - Article

VL - 5

JO - Science Advances

JF - Science Advances

SN - 2375-2548

IS - 5

M1 - 7574

ER -