Renal Na,K‐ATPase Structure from Cryo‐electron Microscopy of Two‐Dimensional Crystals

Hebert, Hans; Purhonen, Pasi; Thomsen, Kristine Rømer; Vorum, Henrik; Maunsbach, Arvid B.

doi:10.1111/j.1749-6632.2003.tb07132.x

Cited by 33 publications

(40 citation statements)

References 26 publications

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“…Since high resolution crystal structures of the Na,Kor H,K ATPase have yet to be described, the exact location of the β subunit is not known. It is thought that there is close interaction on the luminal surface with the entry of TM8 into the membrane domain [47,48] and that perhaps the membrane domain of the β subunit is interdigitated between TM9 and TM10 [49].…”

Section: Tertiary Structurementioning

confidence: 99%

Molecular mechanisms in therapy of acid-related diseases

Shin

Vagin

Munson

et al. 2007

Cell. Mol. Life Sci.

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Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogenpotassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists.

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Section: Tertiary Structurementioning

confidence: 99%

Molecular mechanisms in therapy of acid-related diseases

Shin

Vagin

Munson

et al. 2007

Cell. Mol. Life Sci.

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“…Spans M8 to M10 show relatively small changes in the known conformations and may 1 Abbreviations: srCa ATPase, sarcoplasmic reticulum Ca 2+ -ATPase; omeprazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole; protein-bound form of pantoprazole, [1-(5-difluoromethoxy-1H-benzimidazol-2-yl)-3,4-dimethoxypridinium-2-yl]methyldisulfidyl protein; SCH28080, 3-cyanomethyl-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine; Byk99, (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2- Considerable effort in the past decade utilizing several site-directed mutations and analysis of chimeras has supported many other structure-function generalizations for the P 2 -type ATPases (2,26,27). The rearrangement of the three cytoplasmic domains in the E 1 to E 2 transition and the associated changes in the orientation of the membrane helices implied by the various srCa ATPase crystal structures are believed to be generally conserved (28,29). This assumption has provided the foundation of structure-function analyses for the potassium counter-transport ATPases (12,26,30,31).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 97%

“…The rearrangement of the three cytoplasmic domains in the E 1 to E 2 transition and the associated changes in the orientation of the membrane helices implied by the various srCa ATPase crystal structures are believed to be generally conserved (28,29). This assumption has provided the foundation of structure-function analyses for the potassium counter-transport ATPases (12,26,30,31).…”

mentioning

confidence: 99%

Analysis of the Gastric H,K ATPase for Ion Pathways and Inhibitor Binding Sites

2007

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New models of the gastric H,K ATPase in the E 1 K and E 2 P states are presented as the first structures of a K + counter-transport P 2 -type ATPase exhibiting ion entry and exit paths. Homology modeling was first used to generate a starting conformation from the srCa ATPase E 2 P form (PDB code 1wpg) that contains bound MgADP. Energy minimization of the model showed a conserved adenosine site but nonconserved polyphosphate contacts compared to the srCa ATPase. Molecular dynamics was then employed to expand the luminal entry sufficiently to allow access of the rigid K + competitive naphthyridine inhibitor, Byk99, to its binding site within the membrane domain. The new E 2 P model had increased separation between transmembrane segments M3 through M8, and addition of water in this space showed not only an inhibitor entry path to the luminal vestibule but also a channel leading to the ion binding site. Addition of K + to the hydrated channel with molecular dynamics modeling of ion movement identified a pathway for K + from the lumen to the ion binding site to give E 2 K. A K + exit path to the cytoplasm operating during the normal catalytic cycle is also proposed on the basis of an E 1 K homology model derived from the E 1 2Ca 2+ form of the srCa ATPase (PDB code 1su4). Autodock analyses of the new E 2 P model now correctly discriminate between high-and low-affinity K + competitive inhibitors. Finally, the expanded luminal vestibule of the E 2 P model explains high-affinity ouabain binding in a mutant of the H,K ATPase P 2 -type ATPases (ion pumps) catalyze active ion transport by coupling autophosphorylation and dephosphorylation to ion movement across lipid bilayers. The Na,K ATPases and the gastric H,K ATPase couple outward transport of sodium or protons to the inward transport of potassium. They are distinguished from the other members of this family by the presence of a glycosylated β subunit tightly bound to the larger catalytic (α) subunit and by the need for K + on their luminal surface for completion of the catalytic cycle. There is about 62% homology between their α subunits and about 35% homology between the gastric β subunit and the Na,K ATPase β 2 isoform (1). The α subunits contain the known binding sites for ATP, ions, and inhibitors. Several avenues of research have defined the biochemical features of the shared transport mechanism (2). Transport is achieved through a series of conformational transitions which alternatively bind the transported ions from the cytoplasm in the E 1 form or from the lumen after autophosphorylation from ATP to give the E 2 P conformer. Conversion to E 2 P is associated with export of the outbound cation with generation of luminal acid in the case of the H,K ATPase. For Na,K and H,K ATPases binding of potassium activates dephosphorylation to give a state with tightly bound ion (E 2 K occluded) in equilibrium with † Supported in part by the U.S. Veterans Administration and NIH Grants DK46917, DK53462, and DK58333. *Corresponding author. . kmunson@ucla.edu. ‡ David ...

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“…48.7 nm 2 (Hebert et al 2003). The area S L occupied by one phospholipid molecule in a liquid-crystalline state is approx.…”

Section: Effect Of the Compressibility Of The Proteinmentioning

confidence: 99%

Specific volume and compressibility of bilayer lipid membranes with incorporated Na,K-ATPase

Hianik

Rybár²,

Krivanek³

et al. 2011

gpb

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Abstract. Ultrasound velocimetry and densitometry methods were used to study the interactions of the Na,K-ATPase with the lipid bilayer in large unilamellar liposomes composed of dioleoyl phosphatidylcholine (DOPC). The ultrasound velocity increased and the specific volume of the phospholipids decreased with increasing concentrations of protein. These experiments allowed us to determine the reduced specific apparent compressibility of the lipid bilayer, which decreased by approx. 11% with increasing concentrations of the Na,K-ATPase up to an ATPase/DOPC molar ratio = 2 × 10 -4 . Assuming that ATPase induces rigidization of the surrounding lipid molecules one can obtain from the compressibility data that 3.7 to 100 times more lipid molecules are affected by the protein in comparison with annular lipids. However, this is in contradiction with the current theories of the phase transitions in lipid bilayers. It is suggested that another physical mechanisms should be involved for explanation of observed effect.

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Renal Na,K‐ATPase Structure from Cryo‐electron Microscopy of Two‐Dimensional Crystals

Cited by 33 publications

References 26 publications

Molecular mechanisms in therapy of acid-related diseases

Molecular mechanisms in therapy of acid-related diseases

Analysis of the Gastric H,K ATPase for Ion Pathways and Inhibitor Binding Sites

Specific volume and compressibility of bilayer lipid membranes with incorporated Na,K-ATPase

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