Sandbox11

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This sandbox is in use until August 1, 2011 for UMass Chemistry 423. Others please do not edit this page. Thanks!
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Please use the "3D" button above this box to insert a Jmol applet (molecule) on this page.
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Chem423 Team Projects: Understanding Drug Mechanisms
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Or use the four-green-boxes-button to insert scrollable text adjacent
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to a Jmol applet. Check out the other buttons as well!
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Andy Kim, Zach Brentzel, Tyler Vlass, Zach Hitzig
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{{STRUCTURE_1acj | PDB=1acj | SCENE= }}
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p53 Tumor Supressor gene/HOX gene?
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{{STRUCTURE_1ea5 | PDB=1ea5 | SCENE= }}
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===please do not edit this sandbox unless you are part of La Canada High School Protein DNA Institute===
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=='''Topic: Acetylcholinesterase bound by Tacrine'''==
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== Basic ==
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===this is level 3===
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==Introduction==
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Acetylcholinesterase breaks down acetylcholine into acetic acid and choline via a hydrolysis reaction.<ref>http://www.proteopedia.org/wiki/index.php/Acetylcholinesterase</ref> Acetylcholine is a neurotransmitter that signals muscle contraction. If acetylcholine is not broken down, then the chemical builds up in the synapses between nerve cells and muscle cells resulting in loss of muscle function and ultimately paralysis. The enzyme’s extremely fast reaction rate (approaching the diffusion limit) for breaking one acetylcholine into its two components indicates acetylcholinesterase’s biological importance. Many natural poisons and toxins work by inhibiting this enzyme, thus, paralyzing the victim.<ref>http://www.rcsb.org/pdb/101/motm.do?momID=54</ref>
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Intentionally inhibiting acetylcholinesterase is a treatment for Alzheimer’s disease. Alzheimer’s is basically the progressive breakdown of the nervous system. Worldwide, there are an estimated 20 million individuals diagnosed with Alzheimer’s, most of whom are over the age of 65.<ref>http://www.searo.who.int/en/Section1174/Section1199/Section1567/Section1823_8066.htm</ref> Symptoms of the disease include confusion, irritability and aggressioin, mood swings, language breakdown, long-term memory loss, and eventually loss of bodily functions.<ref>http://en.wikipedia.org/wiki/Alzheimer's_disease</ref> To help combat nerve cell degeneration, these acetylcholinesterase inhibitors partially block the enzyme so that excess neurotransmitters remain in the synapse and strengthen the signal.<ref>http://www.rcsb.org/pdb/101/motm.do?momID=54</ref>
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The drug Tacrine, also known as Cognex, was the first acetylcholinesterase inhibitor approved to treat Alzheimer’s disease. Studies show that the drug only led to slight improvements in people who took it during early stages of the disease, but the drug did nothing to delay the onset of the disease.<ref>http://en.wikipedia.org/wiki/Tacrine</ref> Tacrine is not often used anymore because it has to be taken four times a day and has adverse side effects, including nausea, diarrhea, heartburn, muscle aches and headaches.<ref>http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000930/</ref>
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==Overall structure==
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Acetylcholinesterase (AChE) is an monomeric enzyme. Most often, AChE forms a tetramer and binds with a molecule, collagen Q, to connect to the membrane of the neuromuscular junction. <ref>http://www.ncbi.nlm.nih.gov/pubmed/11804574</ref>. From the <scene name='Sandbox11/Secondary_structure/3'>secondary structure</scene>, it can be seen that there are 17 <scene name='Sandbox11/Alpha_helix_total/4'>alpha helices</scene> and 14 <scene name='Sandbox11/Beta_strands/3'>beta strands</scene>. There are 2 beta sheets formed from 3 anti-parallel and 11 anti-parallel beta sheets, respectively(maybe highlight with green scene). As the <scene name='Sandbox11/Original_structure/3'>overall tertiary structure</scene> shows, turns, alpha helices, and beta sheets all occupy a portion of the exterior of the protein. The means that the turns must be composed primarily of polar side chains. On the other hand, the alpha helices will be amphipathic with side chain order designated by the helical wheel; the exterior will be filled with polar side chains that can hydrogen bond with water while the inside of the alpha helix will have nonpolar, hydrophobic groups. The beta sheets must also be amphipathic, but the pattern of side chains is alternating polar and nonpolar. In addition, in order to maintain its tertiary structure, the protein has three sulfide bonds, which are covalent bonds that form between cysteine. The <scene name='Sandbox11/Disulfide_bond/2'>disulfide bond</scene> between cysteine 67 and cysteine 94 is 5.03 angstroms.
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==Binding==
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The active site of Torpedo californica acetylcholinesterase (TcAChE) is buried at the bottom of a narrow, deep gorge in the enzyme, and contains a <scene name='Sandbox11/Catalytic_triad/6'>catalytic triad</scene> consisting of Ser200, Glu327, and His440. When complexed with tacrine (THA), the aromatic rings of <scene name='Sandbox11/Aromatic_rings_trp_84_phe_330/1'>Trp84 and Phe330</scene> sandwich the THA’s acridine ring . The phenyl ring of Phe330 lies parallel to and in contact with THA. THA is stacked against Trp-84. Its ring nitrogen is H-bonded to the main chain carbonyl oxygen of Hist-440 and it’s amino nitrogen is H-bonded to a water molecule.
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==Additional Features==
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<scene name='Sandbox11/Additional_features_initial/1'>Empty acetylcholinesterase binding gorge,</scene>
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<scene name='Sandbox11/Empty_ach_binding_pocket/9'> the whole AChE,</scene>
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<scene name='Sandbox11/Empty_ach_binding_pocket/5'> stick wireframe,</scene>
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<scene name='Sandbox11/Empty_ach_binding_pocket/10'> rotating.</scene>
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Huperzine A reversible binds with AChE at Ser200 but forms hydrogen bonds with Tyr130, Gly117, and Glu199.<ref>http://www.proteopedia.org/wiki/index.php/AChE_inhibitors_and_substrates_%28Part_II%29</ref>
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<scene name='Sandbox11/Huperzine_a_ache_binding_site/5'>Huperzine A bound at SER 200 site, </scene>
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<scene name='Sandbox11/Huperzine_a_ache_binding_site/4'>stick wireframe, </scene>
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<scene name='Sandbox11/Huperzine_a_ache_binding_site/6'>rotating.</scene>
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Decamethonium is similar to acetylcholine in that it contains trimethylammonium cations allowing it to bind to the nicotinic acetylcholine receptor.<ref>http://en.wikipedia.org/wiki/Decamethonium</ref>
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<scene name='Sandbox11/Decamethonium_ache/4'>Decamethonium bound at SER 200 site, </scene>
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<scene name='Sandbox11/Decamethonium_ache/6'>stick wireframe, </scene>
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<scene name='Sandbox11/Decamethonium_ache/5'>rotating.</scene>
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Soman binds to Ser200, in the active gorge. After binding the acetylcholinesterase(AChE) catalyzes the cleavage of the ether bond on the carbon side causing irreversible inhibition.<ref>http://www.proteopedia.org/wiki/index.php/AChE_inhibitors_and_substrates</ref>
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<scene name='Sandbox11/Nerve_agent_ache/3'>Nerve agent GD(soman) at gorge, </scene>
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<scene name='Sandbox11/Nerve_agent_ache/2'>stick wireframe, </scene>
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<scene name='Sandbox11/Nerve_agent_ache/4'>rotating.</scene>
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Rivastigmine reversible inhibits AChE, binding at the active gorge. The AChE cleaves the rivastigmine into carbamyl moiety and NAP.<ref>http://www.proteopedia.org/wiki/index.php/AChE_inhibitors_and_substrates_%28Part_III%29</ref>
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<scene name='Sandbox11/Rivastigmine_ache/3'>Rivastigmine bound at SER 200 site, </scene>
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<scene name='Sandbox11/Rivastigmine_ache/2'>stick wireframe, </scene>
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<scene name='Sandbox11/Rivastigmine_ache/4'>rotating.</scene>
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==References==
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{{reflist}}
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==Credits==
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Introduction - Tyler Vlass
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Overall Structure - Zach Brentzel
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Drug Binding Site - Andy Kim
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Additional Features - Zach Hitzig
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Current revision

p53 Tumor Supressor gene/HOX gene?

please do not edit this sandbox unless you are part of La Canada High School Protein DNA Institute

Basic

this is level 3

this is text

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