User:Alisha, Deepa, Pamiz/Sandbox 1: Difference between revisions

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[[Image: pump.jpg|300px|left|thumb| '''H+/K+-ATPase pump''' The signals (acetylcholine, histamine, and gastrin) activate the pump in order for the vesicles to move toward the lumen of the stomach.9 These signals bind to their corresponding receptors and activate the cAMP dependent pathway and the Ca2+ dependent pathway.9 Increased levels of intracellular Ca2+ and cAMP will promote the translocation of vesicles to the canalicular membrane, activating the H+/K+-ATPase.9 Histamine binds to a receptor (Histamine H2), and sends a signal through a G protein which activates adenylate cyclase, and catalyzes the conversion of ATP to cAMP.9 Gastrin will stimulate the release of histamine by binding to the gastrin receptor (CCK2).9 Acetylcholine binds to a receptor (Muscarinic M3) and releases Ca2+ from the endoplasmic reticulum.9]]

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== Drug-Molecule Interaction ==

The interaction between Esomeprazole and H+/K+-ATPase has not yet been crystallized.15 Data obtained from the crystallized structure of a '''SCH28080-ATPase''' provides structural and binding site information.16 SCH28080 is a competitive K+ inhibitor that interacts with the enzyme’s Phe126 residue and prevents disulfide bond formation between Omeprazole and Cys813, suggesting mutually exclusive inhibitions and an overlapping binding site.16 The crystallized structure of SCH28080-ATPase shows the same luminal-open (E2) conformation as Esomeprazole, and is the first and only crystallized evidence of PPI-ATPase binding site and conformational change.16 Using this information, the SCH28080-ATPase crystallized structure provides evidence of the two binding sites, Cys813 and Cys892.15,16

The binding pocket, as proposed using SCH28080 includes the following residues: Glu936, Lys791, Glu795, Cys813, Cys892, Phe126, and Glu822 (Figure 5). The negatively charged residues within the TM domains are important for K+ binding and are conserved in all P-type ATPases.16 The SCH28080 model shows that electrostatic and hydrophobic factors affect drug-enzyme interaction.16[[Image:pymol.jpg|300px|left|thumb| '''Crystalized Structure of H+/K+-ATPase ''' TM helices 5,6,7,8 are each highlighted in a different color; the majority of the A & B domain within the enzyme, non-catalytic portions of the enzyme, and SCH28080 have been omitted. The figure depicts the proposed binding sites of the crystallized structure of H+/K+-ATPase. Cys813 and Cys892 are highlighted as the two disulfide bond formation sites. Cys 813 is found between TM5 and TM6 domains while Cys892 is between TM7 and TM8 domains.14 Sulfenamide will interact with these two residues and form disulfide bonds. ]][[Image:pymol_2.jpg|300px|right|thumb| '''Binding pocket of SCH28080-ATPase complex''' PDB image obtained from the RCSB Protein Data Bank.15 Image created using PyMol™ Molecular Graphics System. Glu936 (orange), Glu822 (orange), Lys791 (yellow), Glu 795 (orange), Phe126 (gray), Cys892 (light blue), and Cys813 (light blue) are proposed to be part of Esomeprazole’s binding cavity.15,16 ]]

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 [[Image: pump.jpg|300px|left|thumb| '''H+/K+-ATPase pump''' The signals (acetylcholine, histamine, and gastrin) activate the pump in order for the vesicles to move toward the lumen of the stomach.9 These signals bind to their corresponding receptors and activate the cAMP dependent pathway and the Ca2+ dependent pathway.9 Increased levels of intracellular Ca2+ and cAMP will promote the translocation of vesicles to the canalicular membrane, activating the H+/K+-ATPase.9 Histamine binds to a receptor (Histamine H2), and sends a signal through a G protein which activates adenylate cyclase, and catalyzes the conversion of ATP to cAMP.9 Gastrin will stimulate the release of histamine by binding to the gastrin receptor (CCK2).9 Acetylcholine binds to a receptor (Muscarinic M3) and releases Ca2+ from the endoplasmic reticulum.9]]
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 == Drug-Molecule Interaction ==
 The interaction between Esomeprazole and H+/K+-ATPase has not yet been crystallized.15 Data obtained from the crystallized structure of a '''SCH28080-ATPase''' provides structural and binding site information.16 SCH28080 is a competitive K+ inhibitor that interacts with the enzyme’s Phe126 residue and prevents disulfide bond formation between Omeprazole and Cys813, suggesting mutually exclusive inhibitions and an overlapping binding site.16 The crystallized structure of SCH28080-ATPase shows the same luminal-open (E2) conformation as Esomeprazole, and is the first and only crystallized evidence of PPI-ATPase binding site and conformational change.16 Using this information, the SCH28080-ATPase crystallized structure provides evidence of the two binding sites, Cys813 and Cys892.15,16
 The binding pocket, as proposed using SCH28080 includes the following residues: Glu936, Lys791, Glu795, Cys813, Cys892, Phe126, and Glu822 (Figure 5). The negatively charged residues within the TM domains are important for K+ binding and are conserved in all P-type ATPases.16 The SCH28080 model shows that electrostatic and hydrophobic factors affect drug-enzyme interaction.16[[Image:pymol.jpg|300px|left|thumb| '''Crystalized Structure of H+/K+-ATPase ''' TM helices 5,6,7,8 are each highlighted in a different color; the majority of the A & B domain within the enzyme, non-catalytic portions of the enzyme, and SCH28080 have been omitted. The figure depicts the proposed binding sites of the crystallized structure of H+/K+-ATPase. Cys813 and Cys892 are highlighted as the two disulfide bond formation sites. Cys 813 is found between TM5 and TM6 domains while Cys892 is between TM7 and TM8 domains.14 Sulfenamide will interact with these two residues and form disulfide bonds. ]][[Image:pymol_2.jpg|300px|right|thumb| '''Binding pocket of SCH28080-ATPase complex''' PDB image obtained from the RCSB Protein Data Bank.15 Image created using PyMol™ Molecular Graphics System. Glu936 (orange), Glu822 (orange), Lys791 (yellow), Glu 795 (orange), Phe126 (gray), Cys892 (light blue), and Cys813 (light blue) are proposed to be part of Esomeprazole’s binding cavity.15,16 ]]