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Yuanlin Song - One of the best experts on this subject based on the ideXlab platform.
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Effect of Aquaporin-1 deletion on pleural fluid transport.
Acta pharmacologica Sinica, 2003Co-Authors: Jinjun Jiang, Chunxue Bai, Qun-ying Hong, Min Zhang, Yuanlin SongAbstract:AIM: To investigate the role of Aquaporin-1 (AQP1) and sodium channel on pleural fluid transport. METHODS: Wild-type and AQP1 null mice were used in this study. After the mice were briefly anesthetized, 0.25 mL of hyperosmolar or isosmolar solution (containing terbutaline, amiloride or saline only) was infused into the pleural space. Then mice were sacrificed at scheduled times for measurement of pleural fluid osmolality or volume. RESULTS: After instillation of hyperosmolar fluid into the pleural space, the osmolality of pleural fluid in wild-type mice was higher than that in AQP1 null mice killed at the same time (1, 2, 5 min). There was no difference in the isosmolar clearance between the wild-type and AQP1 null mice after injection of 0.25 mL isosmolar fluid into the pleural space. Terbutaline increased the osmotic and isosmolar fluid transport across pleura, but these effects were not influenced by AQP1 deletion. In contrast, amiloride reduced osmotic and isosmolar pleural fluid transport, and these effects were not influenced by AQP1 deletion. CONCLUSION: AQP1 water channels facilitated osmotic fluid transport across the pleural surface. However, AQP1 did not play an important role in pleural isosmolar fluid clearance. Sodium channel may play a role in osmotic and isosmolar pleural fluid transport. The effects of sodium channel on fluid transport across pleural space were not influenced by Aquaporin-1 deletion.
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Defective dietary fat processing in transgenic mice lacking Aquaporin-1 water channels.
American journal of physiology. Cell physiology, 2001Co-Authors: Sujatha Jayaraman, Kasper S. Wang, Yuanlin Song, Baoxue Yang, J. Augusto Bastidas, Alan S. VerkmanAbstract:Immunocytochemistry showed expression of Aquaporin-1 (AQP1) water channels at sites involved in dietary fat processing, including intrahepatic cholangiocytes, gallbladder, pancreatic microvascular ...
Andreas Engel - One of the best experts on this subject based on the ideXlab platform.
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A refined structure of human Aquaporin-1.
FEBS letters, 2001Co-Authors: Bert L. De Groot, Andreas Engel, Helmut GrubmüllerAbstract:A refined structure of the human water channel Aquaporin-1 is presented. The model rests on the high resolution X-ray structure of the homologous bacterial glycerol transporter GlpF, electron crystallographic data at 3.8 A resolution and a multiple sequence alignment of the Aquaporin superfamily. The crystallographic R and free R values (36.7% and 37.8%) for the refined structure are significantly lower than for previous models. Improved geometry and enhanced stability in molecular dynamics simulations demonstrate a significant improvement of the Aquaporin-1 structure. Comparison with previous Aquaporin-1 models shows significant differences, not only in the loop regions, but also in the core of the water channel.
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Research Letter A re¢ned structure of human Aquaporin-1
2001Co-Authors: Bert L. De Groot, Andreas Engel, Helmut GrubmuAbstract:A refined structure of the human water channel Aquaporin-1 is presented. The model rests on the high resolution X-ray structure of the homologous bacterial glycerol transporter GlpF, electron crystallographic data at 3.8 A O resolution and a multiple sequence alignment of the Aquaporin superfamily. The crystallographic R and free R values (36.7% and 37.8%) for the refined structure are significantly lower than for previous models. Improved geometry and enhanced stability in molecular dynamics simulations demonstrate a significant improvement of the Aquaporin-1 structure. Comparison with previous Aquaporin- 1 models shows significant differences, not only in the loop regions, but also in the core of the water channel. fl 2001 Fed- eration of European Biochemical Societies. Published by Else- vier Science B.V. All rights reserved.
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The fold of human Aquaporin 1.
Journal of molecular biology, 2000Co-Authors: Bert L. De Groot, Kaoru Mitsuoka, Yoshinori Fujiyoshi, Andreas Engel, J. Bernard Heymann, Helmut GrubmüllerAbstract:Abstract The fold of human Aquaporin 1 is determined from cryo-electron microscopic data at 4.5 A resolution. The monomeric structure consists of two transmembrane triple helices arranged around a pseudo-2-fold axis connected by a long flexible extracellular loop. Each triplet contains between its second and third helix a functional loop containing the highly conserved fingerprint NPA motif. These functional loops are assumed to fold inwards between the two triplets, thereby forming the heart of the water channel. The helix topology was determined from the directionality pattern of each of the six transmembrane helices with respect to the membrane, together with constraints defined by the sequence and atomic force microscopy data. The directionality of the helices was determined by collecting the best-fitting orientations resulting from a search through the three-dimensional experimental map for a large number of α-helical fragments. Tests on cryo-electron crystallographic bacteriorhodopsin data suggest that our method is generally applicable to determine the topology of helical proteins for which only medium-resolution electron microscopy data are available.
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The Structure of Aquaporin-1 at 4.5-Å Resolution Reveals Short α-Helices in the Center of the Monomer
Journal of structural biology, 1999Co-Authors: Kaoru Mitsuoka, Thomas Walz, Teruhisa Hirai, Kazuyoshi Murata, Peter Agre, Andreas Engel, J. Bernard Heymann, Yoshinori FujiyoshiAbstract:Abstract Aquaporin-1 is a water channel found in mammalian red blood cells that is responsible for high water permeability of its membrane. Our electron crystallographic analysis of the three-dimensional structure of Aquaporin-1 at 4.5-A resolution confirms the previous finding that each subunit consists of a right-handed bundle of six highly tilted transmembrane helices that surround a central X-shaped structure. In our new potential map, the rod-like densities for the transmembrane helices show helically arranged protrusions, indicating the positions of side chains. Thus, in addition to the six transmembrane helices, observation of helically arranged side-chain densities allowed the identification of two short α-helices representing the two branches of the central X-shaped structure that extend to the extracellular and cytoplasmic membrane surfaces. The other two branches are believed to be loops connecting the short α-helix to a neighboring transmembrane helix. A pore found close to the center of the Aquaporin-1 monomer is suggested to be the course of water flow with implications for the water selectivity.
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the three dimensional structure of Aquaporin 1
Nature, 1997Co-Authors: Thomas Walz, Teruhisa Hirai, Kazuyoshi Murata, Bernard J Heymann, Kaoru Mitsuoka, Yoshinori Fujiyoshi, Barbara L Smith, Peter Agre, Andreas EngelAbstract:The entry and exit of water from cells is a fundamental process of life. Recognition of the high water permeability of red blood cells led to the proposal that specialized water pores exist in the plasma membrane1. Expression in Xenopus oocytes and functional studies of an erythrocyte integral membrane protein of relative molecular mass 28,000, identified it as the mercury-sensitive water channel, Aquaporin-1 (AQP1)2. Many related proteins, all belonging to the major intrinsic protein (MIP) family, are found throughout nature3. AQP1 is a homotetramer containing four independent aqueous channels4,5,6. When reconstituted into lipid bilayers, the protein forms two-dimensional lattices with a unit cell containing two tetramers in opposite orientation7,8,9,10. Here we present the three-dimensional structure of AQP1 determined at 6A resolution by cryo-electron microscopy. Each AQP1 monomer has six tilted, bilayer-spanning α-helices which form a right-handed bundle surrounding a central density. These results, together with functional studies, provide a model that identifies the aqueous pore in the AQP1 molecule and indicates the organization of the tetrameric complex in the membrane.
Klaus Schulten - One of the best experts on this subject based on the ideXlab platform.
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THEORY AND SIMULATION OF WATER PERMEATION IN Aquaporin-1
Biophysical Journal, 2004Co-Authors: Fangqiang Zhu, Emad Tajkhorshid, Klaus SchultenAbstract:We discuss the difference between osmotic permeability pf and diffusion permeability pd of single-file water channels and demonstrate that the pf/pd ratio corresponds to the number of effective steps a water molecule needs to take to permeate a channel. While pd can be directly obtained from equilibrium molecular dynamics simulations, pf can be best determined from simulations in which a chemical potential difference of water has been established on the two sides of the channel. In light of this, we suggest a method to induce in molecular dynamics simulations a hydrostatic pressure difference across the membrane, from which pf can be measured. Simulations using this method are performed on Aquaporin-1 channels in a lipid bilayer, resulting in a calculated pf of 7.1 x 10(-14) cm(3)/s, which is in close agreement with observation. Using a previously determined pd value, we conclude that pf/pd for Aquaporin-1 measures approximately 12. This number is explained in terms of channel architecture and conduction mechanism.
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molecular dynamics study of Aquaporin 1 water channel in a lipid bilayer
FEBS Letters, 2001Co-Authors: Fangqiang Zhu, Emad Tajkhorshid, Klaus SchultenAbstract:The Aquaporin-1 water channel was modeled in a palmitoyl-oleoyl-phosphatidyl-choline lipid bilayer, by means of molecular dynamics simulations. Interaction of the protein with the membrane and inter-monomer interactions were analyzed. Structural features of the channel important for its biological function, including the Asn-Pro-Ala (NPA) motifs, and the diffusion of water molecules into the channels, were investigated. Simulations revealed the formation of single file water inside the channels for certain relative positions of the NPA motifs.
Yoshinori Fujiyoshi - One of the best experts on this subject based on the ideXlab platform.
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The fold of human Aquaporin 1.
Journal of molecular biology, 2000Co-Authors: Bert L. De Groot, Kaoru Mitsuoka, Yoshinori Fujiyoshi, Andreas Engel, J. Bernard Heymann, Helmut GrubmüllerAbstract:Abstract The fold of human Aquaporin 1 is determined from cryo-electron microscopic data at 4.5 A resolution. The monomeric structure consists of two transmembrane triple helices arranged around a pseudo-2-fold axis connected by a long flexible extracellular loop. Each triplet contains between its second and third helix a functional loop containing the highly conserved fingerprint NPA motif. These functional loops are assumed to fold inwards between the two triplets, thereby forming the heart of the water channel. The helix topology was determined from the directionality pattern of each of the six transmembrane helices with respect to the membrane, together with constraints defined by the sequence and atomic force microscopy data. The directionality of the helices was determined by collecting the best-fitting orientations resulting from a search through the three-dimensional experimental map for a large number of α-helical fragments. Tests on cryo-electron crystallographic bacteriorhodopsin data suggest that our method is generally applicable to determine the topology of helical proteins for which only medium-resolution electron microscopy data are available.
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The Structure of Aquaporin-1 at 4.5-Å Resolution Reveals Short α-Helices in the Center of the Monomer
Journal of structural biology, 1999Co-Authors: Kaoru Mitsuoka, Thomas Walz, Teruhisa Hirai, Kazuyoshi Murata, Peter Agre, Andreas Engel, J. Bernard Heymann, Yoshinori FujiyoshiAbstract:Abstract Aquaporin-1 is a water channel found in mammalian red blood cells that is responsible for high water permeability of its membrane. Our electron crystallographic analysis of the three-dimensional structure of Aquaporin-1 at 4.5-A resolution confirms the previous finding that each subunit consists of a right-handed bundle of six highly tilted transmembrane helices that surround a central X-shaped structure. In our new potential map, the rod-like densities for the transmembrane helices show helically arranged protrusions, indicating the positions of side chains. Thus, in addition to the six transmembrane helices, observation of helically arranged side-chain densities allowed the identification of two short α-helices representing the two branches of the central X-shaped structure that extend to the extracellular and cytoplasmic membrane surfaces. The other two branches are believed to be loops connecting the short α-helix to a neighboring transmembrane helix. A pore found close to the center of the Aquaporin-1 monomer is suggested to be the course of water flow with implications for the water selectivity.
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the three dimensional structure of Aquaporin 1
Nature, 1997Co-Authors: Thomas Walz, Teruhisa Hirai, Kazuyoshi Murata, Bernard J Heymann, Kaoru Mitsuoka, Yoshinori Fujiyoshi, Barbara L Smith, Peter Agre, Andreas EngelAbstract:The entry and exit of water from cells is a fundamental process of life. Recognition of the high water permeability of red blood cells led to the proposal that specialized water pores exist in the plasma membrane1. Expression in Xenopus oocytes and functional studies of an erythrocyte integral membrane protein of relative molecular mass 28,000, identified it as the mercury-sensitive water channel, Aquaporin-1 (AQP1)2. Many related proteins, all belonging to the major intrinsic protein (MIP) family, are found throughout nature3. AQP1 is a homotetramer containing four independent aqueous channels4,5,6. When reconstituted into lipid bilayers, the protein forms two-dimensional lattices with a unit cell containing two tetramers in opposite orientation7,8,9,10. Here we present the three-dimensional structure of AQP1 determined at 6A resolution by cryo-electron microscopy. Each AQP1 monomer has six tilted, bilayer-spanning α-helices which form a right-handed bundle surrounding a central density. These results, together with functional studies, provide a model that identifies the aqueous pore in the AQP1 molecule and indicates the organization of the tetrameric complex in the membrane.
Bert L. De Groot - One of the best experts on this subject based on the ideXlab platform.
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discovery of novel human Aquaporin 1 blockers
ACS Chemical Biology, 2013Co-Authors: Daniel Seeliger, Cinta Zapater, Dawid Krenc, Rose Haddoub, Sabine L Flitsch, Eric Beitz, Joan Cerda, Bert L. De GrootAbstract:Human Aquaporin-1 (hAQP1) is a water channel found in many tissues and potentially involved in several human pathologies. Selective inhibitors of hAQP1 are discussed as novel treatment opportunities for glaucoma, brain edema, inflammatory pain, and certain types of cancer. However, only very few potent and chemically attractive blockers have been reported to date. In this study we present three novel hAQP1 blockers that have been identified by virtual screening and inhibit water flux through hAQP1 in Xenopus laevis oocyte swelling assays at low micromolar concentrations. The newly discovered compounds display no chemical similarity to hitherto known hAQP1 blockers and bind at the extracellular entrance of the channel, close to the ar/R selectivity filter. Futhermore, mutagenesis studies showed that Lys36, which is not conserved among the hAQP family, is crucially involved in binding and renders the discovered compounds suitable as leads for the development of selective hAQP1 inhibitors.
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Is TEA an inhibitor for human Aquaporin-1?
Pflugers Archiv : European journal of physiology, 2008Co-Authors: E. Matthias Müller, Jochen S. Hub, Helmut Grubmüller, Bert L. De GrootAbstract:Excessive water uptake through Aquaporins can be life threatening, and disregulation of water permeability causes many diseases. Therefore, reversible Aquaporin inhibitors are highly desired. In this paper, we identified the binding site for tetraethylammonium (TEA) of the membrane water channel Aquaporin-1 by a combined molecular docking and molecular dynamics simulation approach. The binding site identified from docking studies was independently confirmed with an unbiased molecular dynamics simulation of an Aquaporin tetramer embedded in a lipid membrane, surrounded by a 100-mM tetraethylammonium solution in water. A third independent assessment of the binding site was obtained by umbrella sampling simulations. These simulations, in addition, revealed a binding affinity of more than 17 kJ/mol, corresponding to an IC50 value of
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does co2 permeate through Aquaporin 1
Biophysical Journal, 2006Co-Authors: Jochen S. Hub, Bert L. De GrootAbstract:Aquaporins facilitate water permeation across biological membranes. Additionally, glycerol and other small neutral solutes are permeated by related aquaglyceroporins. The role of Aquaporins in gas permeation has been a long- standing and controversially discussed issue. We present an extensive set of atomistic molecular dynamics simulations that address the question of CO2 permeation through human Aquaporin-1. Free energy profiles derived from the simulations display a barrier of ;23 kJ/mol in the aromatic/arginine constriction region of the water pore, whereas a barrier of ;4 kJ/mol was observed for a palmitoyloleoylphosphatidylethanolamine lipid bilayer membrane. The results indicate that significant Aquaporin- 1-mediated CO2 permeation is to be expected only in membranes with a low intrinsic CO2 permeability.
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Does CO2 Permeate through Aquaporin-1?
Biophysical journal, 2006Co-Authors: Jochen S. Hub, Bert L. De GrootAbstract:Aquaporins facilitate water permeation across biological membranes. Additionally, glycerol and other small neutral solutes are permeated by related aquaglyceroporins. The role of Aquaporins in gas permeation has been a long- standing and controversially discussed issue. We present an extensive set of atomistic molecular dynamics simulations that address the question of CO2 permeation through human Aquaporin-1. Free energy profiles derived from the simulations display a barrier of ;23 kJ/mol in the aromatic/arginine constriction region of the water pore, whereas a barrier of ;4 kJ/mol was observed for a palmitoyloleoylphosphatidylethanolamine lipid bilayer membrane. The results indicate that significant Aquaporin- 1-mediated CO2 permeation is to be expected only in membranes with a low intrinsic CO2 permeability.
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A refined structure of human Aquaporin-1.
FEBS letters, 2001Co-Authors: Bert L. De Groot, Andreas Engel, Helmut GrubmüllerAbstract:A refined structure of the human water channel Aquaporin-1 is presented. The model rests on the high resolution X-ray structure of the homologous bacterial glycerol transporter GlpF, electron crystallographic data at 3.8 A resolution and a multiple sequence alignment of the Aquaporin superfamily. The crystallographic R and free R values (36.7% and 37.8%) for the refined structure are significantly lower than for previous models. Improved geometry and enhanced stability in molecular dynamics simulations demonstrate a significant improvement of the Aquaporin-1 structure. Comparison with previous Aquaporin-1 models shows significant differences, not only in the loop regions, but also in the core of the water channel.