Sandbox Reserved 431
From Proteopedia
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The two Arg residues depicted, Arg24 and Arg254, may participate in a salt bridge or a hydrogen bonding interaction with napthoic acid, thus providing a <scene name='Sandbox_Reserved_431/Arg_residues/1'>site 2 ligand</scene>. | The two Arg residues depicted, Arg24 and Arg254, may participate in a salt bridge or a hydrogen bonding interaction with napthoic acid, thus providing a <scene name='Sandbox_Reserved_431/Arg_residues/1'>site 2 ligand</scene>. | ||
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| + | Dephosphorylation of the Tyrosine-Phosphate Residue | ||
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| + | A phosphorylated residue enters the active site of the protein, facilitated by the recognition loop residues Tyr 46 and Val 49. The base of the entrance through which it is brought is known as the PTP loop. The phosphotyrosine entering is amphipathic, thus requiring non-polar pocket for the its phenol ring while the polar end is positioned in the catalytic site. Once inside, the substrate causes a conformational change in the WPD loop, causing the substrate to be help in place for a nucleophilic attack. Also, the residue, Asp 181, is shifted, so that it can act as an acid. Binding in the PTP loop occurs, so the connection between Arg 221 and the phosphate of the substrate is maximized. The WPD loop now has a very stable conformation, as binding has increased with multiple surrounding residues. The tyrosine residue is now positioned in close proximity to the sulfur of Cys 215, allowing Cys 215 to remove the phosphate as an intermediate step in the reaction. The first step of the reaction involves Asp 181 attaching a hydrogen atom to the oxygen of tyrosine, thus neutralizing it and allowing it to diffuse from the site. Next, the phosphate binds to the Cys 215 as described above, forming the cysteinyl-phosphate intermediate. | ||
===Credits=== | ===Credits=== | ||
Revision as of 20:02, 19 April 2012
| This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439. |
Contents |
Phosphatase Inhibitor complexes: pdb 1nny
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Introduction
→ Function: enzyme that decreases the amount of insulin receptor in the cell, which increases the effectiveness of the insulin produced in the body
→ Why important to diabetes: type 2 diabetes is caused by the inability to use insulin effectively. Since phosphatase inhibitors increase the effectiveness of insulin in the cell, it has proved effective in treating type 2 diabetes
→ Nonselective competitive inhibitor
→ Multiple ligand binding sites – inhibitor binds with catalytic site in “open” position. Proves competitive inhibition
→ Formed by being genetically manipulated
Overall Structure
Protein-tyrosine phosphatase - composed of 6 monomers
Each monomer is composed of 283 amino acids
This is NOT the biological unit. Talk to me if you need help with this. Prof T
The monomer has 2 β strands and 10 β sheets - some mixed and some antiparallel and 9 α helices
Binding Interactions
-This is a competitive inhibitor
-It has good selectivity over other phosphatases
-Ligand binds via 2 binding sites
-Binding is reversible
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Additional Features
The two Arg residues depicted, Arg24 and Arg254, may participate in a salt bridge or a hydrogen bonding interaction with napthoic acid, thus providing a .
Dephosphorylation of the Tyrosine-Phosphate Residue
A phosphorylated residue enters the active site of the protein, facilitated by the recognition loop residues Tyr 46 and Val 49. The base of the entrance through which it is brought is known as the PTP loop. The phosphotyrosine entering is amphipathic, thus requiring non-polar pocket for the its phenol ring while the polar end is positioned in the catalytic site. Once inside, the substrate causes a conformational change in the WPD loop, causing the substrate to be help in place for a nucleophilic attack. Also, the residue, Asp 181, is shifted, so that it can act as an acid. Binding in the PTP loop occurs, so the connection between Arg 221 and the phosphate of the substrate is maximized. The WPD loop now has a very stable conformation, as binding has increased with multiple surrounding residues. The tyrosine residue is now positioned in close proximity to the sulfur of Cys 215, allowing Cys 215 to remove the phosphate as an intermediate step in the reaction. The first step of the reaction involves Asp 181 attaching a hydrogen atom to the oxygen of tyrosine, thus neutralizing it and allowing it to diffuse from the site. Next, the phosphate binds to the Cys 215 as described above, forming the cysteinyl-phosphate intermediate.
Credits
Introduction - Jill Carlson
Overall Structure - Polina Berdnikova
Drug Binding Site - Brett Clinton
Additional Features - James Hamblin
