Direct pathogen-induced assembly of an NLR immune receptor complex to form a holoenzyme

Science, Год журнала: 2020, Номер 370(6521)

Опубликована: Дек. 4, 2020

Tetrameric immune receptors Nucleotide-binding/leucine-rich repeat (NLR) detect pathogen effectors and trigger a plant's response. Two groups have now defined the structures of two NLRs that carry Toll-like interleukin-1 receptor (TIR) domains (TIR-NLRs) (see Perspective by Tian Li). Ma et al. studied Arabidopsis thaliana TIR-NLR RPP1 (recognition Peronospora parasitica 1) its response to from an oomycete pathogen. Martin Nicotiana benthamiana ROQ1 XopQ Xanthomonas effector. Both found these TIR-NLRs formed tetramers that, when activated binding effector, exposed active site nicotinamide adenine dinucleoside (NAD) hydrolase. Thus, recognition effector initiates NAD hydrolysis begins Science , this issue p. eabe3069 eabd9993 ; see also 1163

Язык: Английский

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ABC transporters affects tumor immune microenvironment to regulate cancer immunotherapy and multidrug resistance

Drug Resistance Updates, Год журнала: 2022, Номер 66, С. 100905 - 100905

Опубликована: Ноя. 30, 2022

Multidrug resistance (MDR) is the phenomenon in which cancer cells simultaneously develop to a broad spectrum of structurally and mechanistically unrelated drugs. MDR severely hinders effective treatment major cause chemotherapy failure. ATP-binding cassette (ABC) transporters are extensively expressed various body tissues, actively transport endogenous exogenous substrates through biological membranes. Overexpression ABC frequently observed cells, promotes efflux chemotherapeutic drugs reduces their intracellular accumulation. Increasing evidence suggests that regulate tumor immune microenvironment (TIME) by transporting cytokines, thus controlling anti-tumor immunity sensitivity anticancer On other hand, expression regulated cytokines signaling molecules. Targeted inhibition transporter or function can enhance efficacy checkpoint inhibitors promoting microenvironment. This review provides an update on recent research progress this field.

Язык: Английский

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ATP-binding cassette efflux transporters and MDR in cancer

Drug Discovery Today, Год журнала: 2023, Номер 28(5), С. 103537 - 103537

Опубликована: Фев. 16, 2023

Язык: Английский

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ATP‐binding cassette (ABC) transporters in cancer: A review of recent updates

Journal of Evidence-Based Medicine, Год журнала: 2021, Номер 14(3), С. 232 - 256

Опубликована: Авг. 13, 2021

Abstract The ATP‐binding cassette (ABC) transporter superfamily is one of the largest membrane protein families existing in wide spectrum organisms from prokaryotes to human. ABC transporters are also known as efflux pumps because they mediate cross‐membrane transportation various endo‐ and xenobiotic molecules energized by ATP hydrolysis. Therefore, have been considered closely multidrug resistance (MDR) cancer, where structurally distinct chemotherapeutic drugs causes reduced itherapeutic efficacy. Besides, play other critical biological roles cancer such signal transduction. During past decades, extensive efforts made understanding structure‐function relationship, profile transporters, well possibility overcome MDR via targeting these transporters. In this review, we discuss most recent knowledge regarding drug order provide insights for development more effective therapies.

Язык: Английский

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Structures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Июль 19, 2021

ABCG2 is a multidrug transporter that affects drug pharmacokinetics and contributes to resistance of cancer cells. In previously reported structures, the reaction cycle was halted by absence substrates or ATP, mutation catalytic residues, presence small-molecule inhibitors inhibitory antibodies. Here we present cryo-EM structures under turnover conditions containing either endogenous substrate estrone-3-sulfate exogenous topotecan. We find two distinct conformational states in which both transport ATP are bound. Whereas state turnover-1 features more widely separated NBDs an accessible cavity between TMDs, turnover-2 semi-closed almost fully occluded cavity. Substrate size appears control mainly populated. The changes reveal how binding linked closing cytoplasmic side TMDs. transition from likely bottleneck rate-limiting step cycle, where discrimination occurs.

Язык: Английский

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Molecular structure of an open human K _ATP channel

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(48)

Опубликована: Ноя. 23, 2021

Significance ATP-sensitive potassium channel (K ATP ) modulates membrane excitability according to the intracellular metabolic state: a high ATP/ADP ratio increases by closing K + pore, while low reduces opening it. Such intricate regulation is achieved allowing and ADP act upon two different subunits in that exert opposing effects on channel’s gate. Previous structural studies have focused conformations of with closed pore. This paper presents structure an open pore points specific mechanism allosteric regulation.

Язык: Английский

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Highlighting membrane protein structure and function: A celebration of the Protein Data Bank

Journal of Biological Chemistry, Год журнала: 2021, Номер 296, С. 100557 - 100557

Опубликована: Янв. 1, 2021

Biological membranes define the boundaries of cells and compartmentalize chemical physical processes required for life. Many biological are carried out by proteins embedded in or associated with such membranes. Determination membrane protein (MP) structures at atomic near-atomic resolution plays a vital role elucidating their structural functional impact biology. This endeavor has determined 1198 unique MP as early 2021. The value these is expanded greatly deposition three-dimensional (3D) coordinates into Protein Data Bank (PDB) after first structure was elucidated 1985. Since then, free access to facilitates broader deeper understanding MPs, which provides crucial new insights functions. Here we highlight biology representative MPs landmarks evolution technologies, key developments influenced PDB magnifying impact.

Язык: Английский

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A Structure-Based View on ABC-Transporter Linked to Multidrug Resistance

Molecules, Год журнала: 2023, Номер 28(2), С. 495 - 495

Опубликована: Янв. 4, 2023

The discovery of the first ATP-binding cassette (ABC) transporter, whose overexpression in cancer cells is responsible for exporting anticancer drugs out tumor cells, initiated enormous efforts to overcome cell multidrug resistance (MDR) by inhibition ABC-transporter. Because its many physiological functions, diverse studies have been conducted on mechanism, function and regulation this important group transmembrane transport proteins. In review, we will focus structural aspects transporter superfamily. Since resolution revolution electron microscope, experimentally solved structures increased rapidly. A summary available an overview recent structure-based are provided. More specifically, artificial intelligence (AI)-based predictions from AlphaFold-2 be discussed.

Язык: Английский

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Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 5, 2024

Bilirubin is mainly generated from the breakdown of heme when red blood cells reach end their lifespan. Accumulation bilirubin in human body usually leads to various disorders, including jaundice and liver disease. conjugated hepatocytes excreted bile duct via ATP-binding cassette transporter ABCC2, dysfunction which would lead Dubin-Johnson syndrome. Here we determine structures ABCC2 apo, substrate-bound ATP/ADP-bound forms using cryo-electron microscopy, exhibiting a full with regulatory (R) domain inserted between two half modules. Combined substrate-stimulated ATPase transport activity assays, structural analysis enables us figure out cycle R adopting conformations. At rest state, binding translocation cavity functions as an affinity filter that allows substrates high be transported priority. Upon substrate binding, expelled docks lateral transmembrane following ATP hydrolysis. Our findings provide insights into mechanism ABC transporters finely tuned by domain.

Язык: Английский

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Endomembrane-biased dimerization of ABCG16 and ABCG25 transporters determines their substrate selectivity in ABA-regulated plant growth and stress responses

Molecular Plant, Год журнала: 2024, Номер 17(3), С. 478 - 495

Опубликована: Фев. 7, 2024

Язык: Английский

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