The Experts below are selected from a list of 5175 Experts worldwide ranked by ideXlab platform
Jose D Faraldogomez - One of the best experts on this subject based on the ideXlab platform.
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structural and energetic basis for h versus na Binding Selectivity in atp synthase fo rotors
Biochimica et Biophysica Acta, 2010Co-Authors: Alexander Krah, Denys Pogoryelov, Julian D Langer, Peter J Bond, Thomas Meier, Jose D FaraldogomezAbstract:The functional mechanism of the F1Fo ATP synthase, like many membrane transporters and pumps, entails a conformational cycle that is coupled to the movement of H+ or Na+ ions across its transmembrane domain, down an electrochemical gradient. This coupling is an efficient means of energy transduction and regulation, provided that ion Binding to the membrane domain, known as Fo, is appropriately selective. In this study we set out to establish the structural and energetic basis for the ion-Binding Selectivity of the membrane-embedded Fo rotors of two representative ATP synthases. First, we use a biochemical approach to demonstrate the inherent Binding Selectivity of these rotors, that is, independently from the rest of the enzyme. We then use atomically detailed computer simulations of wild-type and mutagenized rotors to calculate and rationalize their Selectivity, on the basis of the structure, dynamics and coordination chemistry of the Binding sites. We conclude that H+ Selectivity is most likely a robust property of all Fo rotors, arising from the prominent presence of a conserved carboxylic acid and its intrinsic chemical propensity for protonation, as well as from the structural plasticity of the Binding sites. In H+-coupled rotors, the incorporation of hydrophobic side chains to the Binding sites enhances this inherent H+ Selectivity. Size restriction may also favor H+ over Na+, but increasing size alone does not confer Na+ Selectivity. Rather, the degree to which Fo rotors may exhibit Na+ coupling relies on the presence of a sufficient number of suitable coordinating side chains and/or structural water molecules. These ligands accomplish a shift in the relative Binding energetics, which under some physiological conditions may be sufficient to provide Na+ dependence.
George Sachs - One of the best experts on this subject based on the ideXlab platform.
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the Binding Selectivity of vonoprazan tak 438 to the gastric h k atpase
Alimentary Pharmacology & Therapeutics, 2015Co-Authors: David R Scott, Keith Munson, Elizabeth A Marcus, Nils Lambrecht, George SachsAbstract:Summary Background The gastric H+,K+-ATPase is the preferred target for acid suppression. Until recently, the only drugs that effectively inhibited this ATPase were the proton pump inhibitors (PPIs). PPIs are acid-activated prodrugs that require acid protection. Once acid-activated, PPIs bind to cysteines of the ATPase, resulting in covalent, long-lasting inhibition. The short plasma half-life of PPIs and continual de novo synthesis of the H+,K+-ATPase result in difficulty controlling night-time acid secretion. A new alternative to PPIs is the pyrrolo-pyridine, vonoprazan (TAK-438), a potassium-competitive acid blocker (PCAB) that does not require acid protection. In contrast to other PCABs, vonoprazan has a long duration of action, resulting in 24-h control of acid secretion, a high pKa of 9.37 and high affinity (Ki = 3.0 ηmol/L). Aim To determine Binding Selectivity of vonoprazan for the gastric H+,K+-ATPase and to explain its slow dissociation. Methods Gastric gland and parietal cell Binding of vonoprazan was determined radiometrically. Molecular modelling explained the slow dissociation of vonoprazan from the H+,K+-ATPase. Results Vonoprazan binds selectively to the parietal cell, independent of acid secretion. Vonoprazan binds in a luminal vestibule between the surfaces of membrane helices 4, 5 and 6. Exit of the drug to the lumen is hindered by asp137 and asn138 in the loop between TM1 and TM2, which presents an electrostatic barrier to movement of the sulfonyl group of vonoprazan. This may explain its slow dissociation from the H+,K+-ATPase and long-lasting inhibition. Conclusion The Binding model provides a template for design of novel potassium-competitive acid blockers.
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The Binding Selectivity of vonoprazan (TAK‐438) to the gastric H+,K+‐ATPase
Alimentary Pharmacology & Therapeutics, 2015Co-Authors: David R Scott, Keith Munson, Elizabeth A Marcus, Nils Lambrecht, George SachsAbstract:Summary Background The gastric H+,K+-ATPase is the preferred target for acid suppression. Until recently, the only drugs that effectively inhibited this ATPase were the proton pump inhibitors (PPIs). PPIs are acid-activated prodrugs that require acid protection. Once acid-activated, PPIs bind to cysteines of the ATPase, resulting in covalent, long-lasting inhibition. The short plasma half-life of PPIs and continual de novo synthesis of the H+,K+-ATPase result in difficulty controlling night-time acid secretion. A new alternative to PPIs is the pyrrolo-pyridine, vonoprazan (TAK-438), a potassium-competitive acid blocker (PCAB) that does not require acid protection. In contrast to other PCABs, vonoprazan has a long duration of action, resulting in 24-h control of acid secretion, a high pKa of 9.37 and high affinity (Ki = 3.0 ηmol/L). Aim To determine Binding Selectivity of vonoprazan for the gastric H+,K+-ATPase and to explain its slow dissociation. Methods Gastric gland and parietal cell Binding of vonoprazan was determined radiometrically. Molecular modelling explained the slow dissociation of vonoprazan from the H+,K+-ATPase. Results Vonoprazan binds selectively to the parietal cell, independent of acid secretion. Vonoprazan binds in a luminal vestibule between the surfaces of membrane helices 4, 5 and 6. Exit of the drug to the lumen is hindered by asp137 and asn138 in the loop between TM1 and TM2, which presents an electrostatic barrier to movement of the sulfonyl group of vonoprazan. This may explain its slow dissociation from the H+,K+-ATPase and long-lasting inhibition. Conclusion The Binding model provides a template for design of novel potassium-competitive acid blockers.
Alexander Krah - One of the best experts on this subject based on the ideXlab platform.
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structural and energetic basis for h versus na Binding Selectivity in atp synthase fo rotors
Biochimica et Biophysica Acta, 2010Co-Authors: Alexander Krah, Denys Pogoryelov, Julian D Langer, Peter J Bond, Thomas Meier, Jose D FaraldogomezAbstract:The functional mechanism of the F1Fo ATP synthase, like many membrane transporters and pumps, entails a conformational cycle that is coupled to the movement of H+ or Na+ ions across its transmembrane domain, down an electrochemical gradient. This coupling is an efficient means of energy transduction and regulation, provided that ion Binding to the membrane domain, known as Fo, is appropriately selective. In this study we set out to establish the structural and energetic basis for the ion-Binding Selectivity of the membrane-embedded Fo rotors of two representative ATP synthases. First, we use a biochemical approach to demonstrate the inherent Binding Selectivity of these rotors, that is, independently from the rest of the enzyme. We then use atomically detailed computer simulations of wild-type and mutagenized rotors to calculate and rationalize their Selectivity, on the basis of the structure, dynamics and coordination chemistry of the Binding sites. We conclude that H+ Selectivity is most likely a robust property of all Fo rotors, arising from the prominent presence of a conserved carboxylic acid and its intrinsic chemical propensity for protonation, as well as from the structural plasticity of the Binding sites. In H+-coupled rotors, the incorporation of hydrophobic side chains to the Binding sites enhances this inherent H+ Selectivity. Size restriction may also favor H+ over Na+, but increasing size alone does not confer Na+ Selectivity. Rather, the degree to which Fo rotors may exhibit Na+ coupling relies on the presence of a sufficient number of suitable coordinating side chains and/or structural water molecules. These ligands accomplish a shift in the relative Binding energetics, which under some physiological conditions may be sufficient to provide Na+ dependence.
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Structural and energetic basis for H+ versus Na+ Binding Selectivity in ATP synthase Fo rotors.
Biochimica et Biophysica Acta, 2010Co-Authors: Alexander Krah, Denys Pogoryelov, Julian D Langer, Peter J Bond, Thomas Meier, José D. Faraldo-gómezAbstract:The functional mechanism of the F1Fo ATP synthase, like many membrane transporters and pumps, entails a conformational cycle that is coupled to the movement of H+ or Na+ ions across its transmembrane domain, down an electrochemical gradient. This coupling is an efficient means of energy transduction and regulation, provided that ion Binding to the membrane domain, known as Fo, is appropriately selective. In this study we set out to establish the structural and energetic basis for the ion-Binding Selectivity of the membrane-embedded Fo rotors of two representative ATP synthases. First, we use a biochemical approach to demonstrate the inherent Binding Selectivity of these rotors, that is, independently from the rest of the enzyme. We then use atomically detailed computer simulations of wild-type and mutagenized rotors to calculate and rationalize their Selectivity, on the basis of the structure, dynamics and coordination chemistry of the Binding sites. We conclude that H+ Selectivity is most likely a robust property of all Fo rotors, arising from the prominent presence of a conserved carboxylic acid and its intrinsic chemical propensity for protonation, as well as from the structural plasticity of the Binding sites. In H+-coupled rotors, the incorporation of hydrophobic side chains to the Binding sites enhances this inherent H+ Selectivity. Size restriction may also favor H+ over Na+, but increasing size alone does not confer Na+ Selectivity. Rather, the degree to which Fo rotors may exhibit Na+ coupling relies on the presence of a sufficient number of suitable coordinating side chains and/or structural water molecules. These ligands accomplish a shift in the relative Binding energetics, which under some physiological conditions may be sufficient to provide Na+ dependence.
David R Scott - One of the best experts on this subject based on the ideXlab platform.
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the Binding Selectivity of vonoprazan tak 438 to the gastric h k atpase
Alimentary Pharmacology & Therapeutics, 2015Co-Authors: David R Scott, Keith Munson, Elizabeth A Marcus, Nils Lambrecht, George SachsAbstract:Summary Background The gastric H+,K+-ATPase is the preferred target for acid suppression. Until recently, the only drugs that effectively inhibited this ATPase were the proton pump inhibitors (PPIs). PPIs are acid-activated prodrugs that require acid protection. Once acid-activated, PPIs bind to cysteines of the ATPase, resulting in covalent, long-lasting inhibition. The short plasma half-life of PPIs and continual de novo synthesis of the H+,K+-ATPase result in difficulty controlling night-time acid secretion. A new alternative to PPIs is the pyrrolo-pyridine, vonoprazan (TAK-438), a potassium-competitive acid blocker (PCAB) that does not require acid protection. In contrast to other PCABs, vonoprazan has a long duration of action, resulting in 24-h control of acid secretion, a high pKa of 9.37 and high affinity (Ki = 3.0 ηmol/L). Aim To determine Binding Selectivity of vonoprazan for the gastric H+,K+-ATPase and to explain its slow dissociation. Methods Gastric gland and parietal cell Binding of vonoprazan was determined radiometrically. Molecular modelling explained the slow dissociation of vonoprazan from the H+,K+-ATPase. Results Vonoprazan binds selectively to the parietal cell, independent of acid secretion. Vonoprazan binds in a luminal vestibule between the surfaces of membrane helices 4, 5 and 6. Exit of the drug to the lumen is hindered by asp137 and asn138 in the loop between TM1 and TM2, which presents an electrostatic barrier to movement of the sulfonyl group of vonoprazan. This may explain its slow dissociation from the H+,K+-ATPase and long-lasting inhibition. Conclusion The Binding model provides a template for design of novel potassium-competitive acid blockers.
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The Binding Selectivity of vonoprazan (TAK‐438) to the gastric H+,K+‐ATPase
Alimentary Pharmacology & Therapeutics, 2015Co-Authors: David R Scott, Keith Munson, Elizabeth A Marcus, Nils Lambrecht, George SachsAbstract:Summary Background The gastric H+,K+-ATPase is the preferred target for acid suppression. Until recently, the only drugs that effectively inhibited this ATPase were the proton pump inhibitors (PPIs). PPIs are acid-activated prodrugs that require acid protection. Once acid-activated, PPIs bind to cysteines of the ATPase, resulting in covalent, long-lasting inhibition. The short plasma half-life of PPIs and continual de novo synthesis of the H+,K+-ATPase result in difficulty controlling night-time acid secretion. A new alternative to PPIs is the pyrrolo-pyridine, vonoprazan (TAK-438), a potassium-competitive acid blocker (PCAB) that does not require acid protection. In contrast to other PCABs, vonoprazan has a long duration of action, resulting in 24-h control of acid secretion, a high pKa of 9.37 and high affinity (Ki = 3.0 ηmol/L). Aim To determine Binding Selectivity of vonoprazan for the gastric H+,K+-ATPase and to explain its slow dissociation. Methods Gastric gland and parietal cell Binding of vonoprazan was determined radiometrically. Molecular modelling explained the slow dissociation of vonoprazan from the H+,K+-ATPase. Results Vonoprazan binds selectively to the parietal cell, independent of acid secretion. Vonoprazan binds in a luminal vestibule between the surfaces of membrane helices 4, 5 and 6. Exit of the drug to the lumen is hindered by asp137 and asn138 in the loop between TM1 and TM2, which presents an electrostatic barrier to movement of the sulfonyl group of vonoprazan. This may explain its slow dissociation from the H+,K+-ATPase and long-lasting inhibition. Conclusion The Binding model provides a template for design of novel potassium-competitive acid blockers.
Thomas Meier - One of the best experts on this subject based on the ideXlab platform.
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structural and energetic basis for h versus na Binding Selectivity in atp synthase fo rotors
Biochimica et Biophysica Acta, 2010Co-Authors: Alexander Krah, Denys Pogoryelov, Julian D Langer, Peter J Bond, Thomas Meier, Jose D FaraldogomezAbstract:The functional mechanism of the F1Fo ATP synthase, like many membrane transporters and pumps, entails a conformational cycle that is coupled to the movement of H+ or Na+ ions across its transmembrane domain, down an electrochemical gradient. This coupling is an efficient means of energy transduction and regulation, provided that ion Binding to the membrane domain, known as Fo, is appropriately selective. In this study we set out to establish the structural and energetic basis for the ion-Binding Selectivity of the membrane-embedded Fo rotors of two representative ATP synthases. First, we use a biochemical approach to demonstrate the inherent Binding Selectivity of these rotors, that is, independently from the rest of the enzyme. We then use atomically detailed computer simulations of wild-type and mutagenized rotors to calculate and rationalize their Selectivity, on the basis of the structure, dynamics and coordination chemistry of the Binding sites. We conclude that H+ Selectivity is most likely a robust property of all Fo rotors, arising from the prominent presence of a conserved carboxylic acid and its intrinsic chemical propensity for protonation, as well as from the structural plasticity of the Binding sites. In H+-coupled rotors, the incorporation of hydrophobic side chains to the Binding sites enhances this inherent H+ Selectivity. Size restriction may also favor H+ over Na+, but increasing size alone does not confer Na+ Selectivity. Rather, the degree to which Fo rotors may exhibit Na+ coupling relies on the presence of a sufficient number of suitable coordinating side chains and/or structural water molecules. These ligands accomplish a shift in the relative Binding energetics, which under some physiological conditions may be sufficient to provide Na+ dependence.
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Structural and energetic basis for H+ versus Na+ Binding Selectivity in ATP synthase Fo rotors.
Biochimica et Biophysica Acta, 2010Co-Authors: Alexander Krah, Denys Pogoryelov, Julian D Langer, Peter J Bond, Thomas Meier, José D. Faraldo-gómezAbstract:The functional mechanism of the F1Fo ATP synthase, like many membrane transporters and pumps, entails a conformational cycle that is coupled to the movement of H+ or Na+ ions across its transmembrane domain, down an electrochemical gradient. This coupling is an efficient means of energy transduction and regulation, provided that ion Binding to the membrane domain, known as Fo, is appropriately selective. In this study we set out to establish the structural and energetic basis for the ion-Binding Selectivity of the membrane-embedded Fo rotors of two representative ATP synthases. First, we use a biochemical approach to demonstrate the inherent Binding Selectivity of these rotors, that is, independently from the rest of the enzyme. We then use atomically detailed computer simulations of wild-type and mutagenized rotors to calculate and rationalize their Selectivity, on the basis of the structure, dynamics and coordination chemistry of the Binding sites. We conclude that H+ Selectivity is most likely a robust property of all Fo rotors, arising from the prominent presence of a conserved carboxylic acid and its intrinsic chemical propensity for protonation, as well as from the structural plasticity of the Binding sites. In H+-coupled rotors, the incorporation of hydrophobic side chains to the Binding sites enhances this inherent H+ Selectivity. Size restriction may also favor H+ over Na+, but increasing size alone does not confer Na+ Selectivity. Rather, the degree to which Fo rotors may exhibit Na+ coupling relies on the presence of a sufficient number of suitable coordinating side chains and/or structural water molecules. These ligands accomplish a shift in the relative Binding energetics, which under some physiological conditions may be sufficient to provide Na+ dependence.
