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Revision as of 16:29, 17 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 |
1-JVQ: Devourer of Memories
Introduction
Dementia sucks. Slowly losing one's mind is no fun, and it is especially hard on the people who have to watch it happen to one of their loved ones. We can all agree that dementia is a disease worth curing: to do that we must first determine its cause. The most likely culprit for the cause of dementias are a group of protease inhibitors called serpins. Serpins are an unusual group as inhibitors go because while most inhibitors simply block the binding site, serpins undergo conformational changes when they bind. Mutations can alter those conformational changes. When this happens, the serpins can no longer function as inhibitors. This can lead to a massive buildup of mutated proteins in the cell, eventually killing it. In addition, the mutated serpins can polymerize, creating long chains that can do a great deal of damage to anything they come in contact with. After the cell is destroyed, the mutant inhibitor polymers continue to grow, spreading throughout the surrounding tissue, eventually resulting in organ failure. Mutations in the conformational structure of neuroserpin, a protease inhibitor found in neurons, has been blamed for the deterioration of brain function seen in dementia.
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Overall Structure
General Overview (alpha-beta arrangements, number of strands etc.)
polymerization binding site
peptide anchor
design of polymerization inhibitors?
Binding Interactions
WMDF - tetra peptide with bulky side chains
WMDF binds to P14-8 peptide-antithrombin binary complex
-Tetra peptide occupies P7-P4 vacancy -Forms 8 hydrogen bonds with adjacent residues
Methionine is at the P6 location, while phenylalanine is at P4 location
-P4 & P6 locations are very critical
-Hydrophobicity of P4 & P6 are consistent feature of effective serpin-derived peptides
-results in a shift of the connecting loop when compared to latent antithrombin
-Successfully inhibits antithrombin polymerisation
Additional Features
10 million of European decent carry Z-allele of antitrypsin
-means 50% of antitrypsin polymerises -only a concern if exeeds limit of threshold
Therapeutic Techniques
-tip equilibrium towards dissociation -use of protiens to bind to more receptive and unstable form of the protein -this can hinder/prevent oligomer formation
Found out can block with smaller peptides
-3 to 4 residues instead of 6+ -small enough to give us a model for designing mimics that are not peptides
Glycerol is a molecule that can bind like this
-binds to site critical for polymerization -although one is not enough, many can be used to block
Credits
Introduction - Kevin Dillon
Overall Structure - Max Nowak
Drug Binding Site - Kyle Reed
Additional Features - Chris Carr
