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Revision as of 20:55, 27 September 2010
A Physical Model of Acetylcholinesterase in Complex with Acetylcholine and Fasciculin-IIA Physical Model of Acetylcholinesterase in Complex with Acetylcholine and Fasciculin-II
Students: Mary Acheampong. Daviana Dueno, Bobby Glover, Alafia Henry, Randol Mata, Marisa VanBrakle. Teacher: Allison Granberry Mentors: Joel Sussman, Weissman Institule of Science, and Lars Westblade, touro College of Pharmacy.
AbstractAbstract
Acetylcholinesterase(AChE) is essential for the hydrolysis of the neurotransmitter acetylcholine(ACh) in cholinergic synapses. Irreversible inhibition of AChE can lead to increased levels of ACh and ultimately death. Conversely, suppressed levels of ACh may lead to memory deficits associated with Alzheimer's disease. AChE has a deep(20A) and narrow(5A) gorge lined with 14 aromatic residues, with its active site at the bottom of the gorge. Initially, ACh binds to the peripheral anionic site(PAS) of AChE and is funneled down the gorge to the active site by interactions between the aromatic rings of the 14 aromatic residues and the quaternary ammonium ion of ACh. At the active site, ACh is oriented for hydrolysis by interactions between the catalytic anionic ion site and the quaternary ammonium ion of ACh. The Fasciculin-II(FAS-II)toxin, from the East African Green Mamba snake(Dendroaspis angusticeps) venom, inhibits AChE by binding to the top of the active-site gorge, and thus preventing ACh from entering into it. The Hostos-Lincoln Academy SMART(Students Modeling A Research Topic) team and MSOE have designed and made two physical models by three-dimensional(3D) printing technology: Torpedo californica(Tc) AChE in complex with a modeled ACh ligand and TcAChE in complex with FAS-II.
Designing a Physical Model to Tell the Story of AcetylcholinesteraseDesigning a Physical Model to Tell the Story of Acetylcholinesterase
Reflected in our design are two key concepts of AChE: the biochemistry of how the ACh overcomes the depth of the active site gorge before hydrolysis can occur, and how a toxin inhibits the substrate from finding the active site.Two physical models were designed and made by 3-dimensional printing technology: Torpedo californica (Tc) AChE in complex with a modeled ACh ligand, and Tc AChE in complex with FAS-II. Both models were based on protein data bank (PDB) files, and Rasmol computer modeling program. PDB files included PDB entry code 2ace for the TcAChE/ACh complex, and PDB entry code 1fss for the Tc AChE/FAS-II complex.
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Features of the Substrate Traffic Story: AChE/AChFeatures of the Substrate Traffic Story: AChE/ACh
AChE is an alpha/beta hydrolase fold with an amino acid sequence of 4-535. The alpha carbon backbone in complex with acetylcholine is shown here in green.
The that line the active site gorge are tyr70, trp84, trp120, tyr121, tyr130, trp233, trp279, phe288, phe290, phe330, phe331, tyr334, trp432 and tyr442.
The or active site includes glu327, his440 and ser200. Here is where Acetylcholine is hydrolyzed.
Three of the aromatic residues that line the gorge attract the quaternary ammonium ion of ACh. These 3 aromatic residues, trp279, tyr70, and tyr121, sit at the entrance of the gorge and make up the .
Two of the 14 aromatic residues lining the active site gorge that are considered significant for holding ACh in an optimal position for hydrolysis are trp84 and phe330. These residues form the .
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Features of the Inhibition StoryFeatures of the Inhibition Story
FAS-II were illustrated in an alpha carbon backbone. The alpha carbon backbone of FAS-II has 4 beta sheets forming three loops or fingers.
The are present on two loops of the toxin FAS-II.
When FAS-II to AChE, Arg27 and Met33 interact with trp279 of the Peripheral Anionic Site, while Val34 and Thr8 interact with tyr70 of the Peripheral Anionic Site.