Cryo-EM structure of human ABCB8 transporter in nucleotide binding state

Li, Shunjin; Ren, Yue; Lu, Xuhang; Shen, Yuequan; Yang, Xue

doi:10.1016/j.bbrc.2021.04.007

Cited by 15 publications

(8 citation statements)

References 27 publications

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“…In contrast, most ABC transporters in the ATP-bound state are not able to recognize substrates, as shown for ABCB4 [104] , as these form an outward-facing conformation. Only in exceptional cases an ATP-bound state was observed with an inward-facing conformation, for example, the mitochondrial ABC transporters ABCB8 [126] and ABCB10 [127] . In the case of the lysosomal ABC transporter ABCD4, the outward-facing conformation (bound to two molecules of ATP) was suggested as the actual state of acceptance of the substrate cobalamin [128] .…”

Section: Resultsmentioning

confidence: 99%

Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics

Namasivayam

Stefan

Pahnke

et al. 2021

Computational and Structural Biotechnology Journal

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Section: Resultsmentioning

confidence: 99%

Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics

Namasivayam

Stefan

Pahnke

et al. 2021

Computational and Structural Biotechnology Journal

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“…As a typical ABC transporter, this protein is targeted to mitochondria [23], and is composed of a transmembrane domain and a nucleotide-binding domain. As demonstrated in the crystal structure (PDB number 5OCH), this protein is a dimer that binds nucleotides (ex: ATP and ADP), and the nucleotide-binding domain faces the mitochondrial matrix [24].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, ADP inhibits mitochondrial K+ currents, although with a lower affinity [26]. Interestingly, mitoSUR/ABCB8 binds the non-hydrolyzable ATP analog (ATP-PNP) [24] but this molecule is not capable of inhibiting the mitoKATP [27]. Whether mitoSUR (ABCB8) hydrolyzes GTP or not is not clear yet.…”

Section: Discussionmentioning

confidence: 99%

Competitive interaction between ATP and GTP regulates mitochondrial ATP-sensitive potassium channels

Palácio

Soares

Lima

et al. 2023

Preprint

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Mitochondrial ATP-sensitive K+channels (mitoKATP) have been recently characterized structurally, and possess a protein through which K+enters mitochondria (MitoKIR), and a regulatory subunit (mitoSUR). The mitoSUR regulatory subunit is an ATP-binding cassette (ABC) protein isoform 8 (ABCB8). Opening of these channels is known to be cardioprotective, but the molecular and physiological mechanisms that activate them are not fully known. Here, to better understand the molecular and physiological mechanisms of activators (GTP) and inhibitors (ATP) on the activity of mitoKATP, we exposed isolated mitochondria to both nucleotides. We also used molecular docking directed to the nucleotide-binding domain of human ABCB8/mitoSUR to test a comparative model of ATP and GTP effects. As expected, we find that ATP dose-dependently inhibits mitoKATP activity (IC50 = 21.24 ± 1.4 μM). However, simultaneous exposure of mitochondria to GTP dose-dependently (EC50 = 13.19 ± 1.33 μM) reversed ATP inhibition. Pharmacological and computational studies suggest that GTP reverses ATP activity competitively. Docking directed to the site of crystallized ADP reveals that both nucleotides bind to mitoSUR with high affinity, with their phosphates directed to the Mg2+ion and the walker A motif of the protein (SGGGKTT). These effects, when combined, result in GTP binding, ATP displacement, mitochondrial ATP-sensitive K+transport, and lower formation of reactive oxygen species. Overall, our findings demonstrate the basis for ATP and GTP binding in mitoSUR using a combination of biochemical, pharmacological, and computational experiments. Future studies may reveal the extent to which the balance between ATP and GTP actions contribute toward cardioprotection against ischemic events.

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“…S15C). The cryo-EM structure of MITOSUR (ABCB8) exhibited a dimeric architecture typical of ABC transporters (Li et al , 2021), which lacks the additional transmembrane domain (TMD0) of SUR subunit that interacts with Kir6.2 (Fig. S15D and E).…”

Section: Sars-cov-2 Viroporinsmentioning

confidence: 99%

To be or not to be an ion channel: cryo-EM structures have a say

Chen

Zhang

et al. 2023

Preprint

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Identification of previously unknown ion channels is always a challenging work though the transmembrane protein-coding genes in human genome has been comprehensively annotated for years. Despite being the gold standard of functional assay for ion channels, electrophysiological recordings are often accompanied by electrical noise, leak conductance and background currents of the membrane system. These unwanted signals, if not treated properly, lead to mischaracterization of proteins with seemingly unusual ion-conducting properties. In recent ten years, the technical revolution of cryo-electron microscopy (cryo-EM) have greatly advanced our understanding on the structures and gating mechanisms of various ion channels, and also raised concerns about the pore-forming ability of some previously identified channel proteins. In this review, we summarize cryo-EM findings on ion channels with molecular identities recognized or disputed in recent ten years, and discuss current knowledge of proposed channel proteins awaiting cryo-EM analyses. We also present a classification of ion channels according to their architectures and evolutionary relationships, and discuss the possibility and strategy of identifying more ion channels by analyzing structures of transmembrane proteins of unknown function.

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Cryo-EM structure of human ABCB8 transporter in nucleotide binding state

Cited by 15 publications

References 27 publications

Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics

Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics

Competitive interaction between ATP and GTP regulates mitochondrial ATP-sensitive potassium channels

To be or not to be an ion channel: cryo-EM structures have a say

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