Molecular Mechanism of Acetate Transport through the Acetate Channel SatP

Wu, Meng; Sun, Liping; Zhou, Qingtong; Peng, Yao; Liu, Zhijie; Zhao, Suwen

doi:10.1021/acs.jcim.8b00975

Cited by 9 publications

(25 citation statements)

References 61 publications

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“… 400 Simulations of the structurally related SatP acetate channel showed that water hydrates all parts of the pore, including the central constriction site which forms an energetic barrier for acetate. 401 …”

Section: Aquaporins and Related Water And Polar Solute Poresmentioning

confidence: 99%

Water in Nanopores and Biological Channels: A Molecular Simulation Perspective

2020

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This Review explores the dynamic behavior of water within nanopores and biological channels in lipid bilayer membranes. We focus on molecular simulation studies, alongside selected structural and other experimental investigations. Structures of biological nanopores and channels are reviewed, emphasizing those high-resolution crystal structures, which reveal water molecules within the transmembrane pores, which can be used to aid the interpretation of simulation studies. Different levels of molecular simulations of water within nanopores are described, with a focus on molecular dynamics (MD). In particular, models of water for MD simulations are discussed in detail to provide an evaluation of their use in simulations of water in nanopores. Simulation studies of the behavior of water in idealized models of nanopores have revealed aspects of the organization and dynamics of nanoconfined water, including wetting/dewetting in narrow hydrophobic nanopores. A survey of simulation studies in a range of nonbiological nanopores is presented, including carbon nanotubes, synthetic nanopores, model peptide nanopores, track-etched nanopores in polymer membranes, and hydroxylated and functionalized nanoporous silica. These reveal a complex relationship between pore size/geometry, the nature of the pore lining, and rates of water transport. Wider nanopores with hydrophobic linings favor water flow whereas narrower hydrophobic pores may show dewetting. Simulation studies over the past decade of the behavior of water in a range of biological nanopores are described, including porins and β-barrel protein nanopores, aquaporins and related polar solute pores, and a number of different classes of ion channels. Water is shown to play a key role in proton transport in biological channels and in hydrophobic gating of ion channels. An overall picture emerges, whereby the behavior of water in a nanopore may be predicted as a function of its hydrophobicity and radius. This informs our understanding of the functions of diverse channel structures and will aid the design of novel nanopores. Thus, our current level of understanding allows for the design of a nanopore which promotes wetting over dewetting or vice versa. However, to design a novel nanopore, which enables fast, selective, and gated flow of water de novo would remain challenging, suggesting a need for further detailed simulations alongside experimental evaluation of more complex nanopore systems.

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Section: Aquaporins and Related Water And Polar Solute Poresmentioning

confidence: 99%

Water in Nanopores and Biological Channels: A Molecular Simulation Perspective

2020

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“…Branches that were not relevant were collapsed with the representative genus indicated. (18)(19)(20).…”

Section: Figmentioning

confidence: 99%

“…The Ato1 orthologues in Escherichia coli (ecSatP) and Citrobacter koseri (ckSatP) are so far the only members of the AceTr family whose structures are available (19,49). A hexameric UreI-like channel structure was reported for ecSatP (49); however, more recently, it was suggested that the closed state of the channel represents a relatively high energy barrier, 15 kcal/mol (20). The signature NPAPL GL(M/S) motif of the AceTr family, located at the beginning of the first TMS (Fig.…”

Section: Phylogenetic Evolution Of Ato Transportersmentioning

confidence: 99%

“…Recent structural analyses with the SatP homolog from Citrobacter koseri have demonstrated that these conserved amino acids are in the vicinity of the first and second acetate/succinate-binding sites, allowing the translocation of the substrate (18,19). The dissection of the molecular mechanism of the acetate transport in several members of the AceTr family suggests that these transporters are energy dependent (18,20,36,39,50). This functional motif, as well as other amino acids that play important roles in the transport mechanism of Ato transporters, are highly conserved among all of the identified Candida orthologues, suggesting that Candida Atos are likely to retain the same function (Fig.…”

Section: Phylogenetic Evolution Of Ato Transportersmentioning

confidence: 99%

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Carboxylic Acid Transporters in Candida Pathogenesis

Alves

Sousa-Silva

Vieira

et al. 2020

mBio

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Opportunistic pathogens such as Candida species can use carboxylic acids, like acetate and lactate, to survive and successfully thrive in different environmental niches. These nonfermentable substrates are frequently the major carbon sources present in certain human body sites, and their efficient uptake by regulated plasma membrane transporters plays a critical role in such nutrient-limited conditions. Here, we cover the physiology and regulation of these proteins and their potential role in Candida virulence. This review also presents an evolutionary analysis of orthologues of the Saccharomyces cerevisiae Jen1 lactate and Ady2 acetate transporters, including a phylogenetic analysis of 101 putative carboxylate transporters in twelve medically relevant Candida species. These proteins are assigned to distinct clades according to their amino acid sequence homology and represent the major carboxylic acid uptake systems in yeast. While Jen transporters belong to the sialate:H+ symporter (SHS) family, the Ady2 homologue members are assigned to the acetate uptake transporter (AceTr) family. Here, we reclassify the later members as ATO (acetate transporter ortholog). The new nomenclature will facilitate the study of these transporters, as well as the analysis of their relevance for Candida pathogenesis.

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“…GPCRs at an atomic level and uncovering biomolecular mechanisms that are unattainable by experimental methods [26][27][28][29][30][31][32][33] . Integrating MD simulations with Markov state models (MSMs) [34][35][36] has proven successful in understanding the molecular switches in β2 adrenergic receptor, 37 elucidating ligand-driven conformational changes in CC chemokine receptor 2 38 , and revealing a cryptic pocket in dopamine D3 receptor 39 .…”

Section: Computational Methods Especially Molecular Dynamics (Md) Simentioning

confidence: 99%

Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as novel targets for allosteric drug design

Yang

Chai

et al. 2020

Preprint

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G protein-coupled receptors (GPCRs) are the most frequent targets of approved drugs. A complete mechanistic elucidation of large-scale conformational transitions underlying the activation mechanisms of GPCRs is of critical importance for therapeutic drug development. Here, we utilized a combined computational and experimental framework that integrated extensive molecular dynamics simulations, Markov state models, and site-directed mutagenesis for investigating the conformational landscape of activation of the angiotensin II (AngII) type 1 receptor (AT1R), a prototypical class A GPCR. Our findings suggested a synergistic transition mechanism of AT1R activation. Importantly, a key intermediate state was found in the activation pathway. We discovered a novel “cryptic” binding site in the intracellular region of the receptor in the intermediate state. Furthermore, a bioluminescence resonance energy transfer analysis revealed the insensitivity of the endogenous AngII octapeptide agonist in the activation of the downstream Gq signaling and β-arrestin-mediated pathways, upon mutations of the predicted cryptic binding site, thereby suggesting an allosteric regulatory mechanism. Together, these findings not only provide a deeper understanding of AT1R activation at an atomic level, but also open potential avenues for the design of allosteric AT1R modulators. Consequently, this will provide a broad range of applications for GPCR biology, biophysics, and medicinal chemistry.

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Molecular Mechanism of Acetate Transport through the Acetate Channel SatP

Cited by 9 publications

References 61 publications

Water in Nanopores and Biological Channels: A Molecular Simulation Perspective

Water in Nanopores and Biological Channels: A Molecular Simulation Perspective

Carboxylic Acid Transporters in Candida Pathogenesis

Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as novel targets for allosteric drug design

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