Protein effects on a model for the activation of a serotonin receptor.
Item
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Title
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Protein effects on a model for the activation of a serotonin receptor.
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Identifier
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AAI9009761
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identifier
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9009761
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Creator
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Mercier, Gustavo Alberto.
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Contributor
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Adviser: Harel Weinstein
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Date
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1989
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Language
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English
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Publisher
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City University of New York.
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Subject
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Health Sciences, Pharmacology | Chemistry, Physical | Chemistry, Biochemistry
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Abstract
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A proton transfer (PT) triggered by a ligand interacting with the receptor had been suggested as the initial step in the activation of a serotonin (5-HT) receptor. A new strategy is introduced to evaluate, in the absence of the three dimensional structure of the receptor, the role of the receptor in modulating the activation mechanism. The strategy consists of using proteins of known structure as receptor models to study the effects of the receptor environment on the process of activation. Actinidin, a sulfhydryl proteinase, satisfied the criteria as a model receptor in which to study the effects from the protein environment of the 5-HT/LSD receptor (also known as the 5-HT{dollar}\sb{lcub}\rm 1a{rcub}{dollar} receptor). The results from computations of the PT from His 162 to Cys 25 showed that the electrostatic effect from the protein raises the energy barrier and lowers the driving energy for the proton transfer. This result constitutes a desirable property of the model; otherwise, the receptor would be activated in the absence of agonists. The protein effect results from the interaction with the proton donor and acceptor groups as they changed due to the PT, and not from a direct effect on the proton along its path. Different structural elements in actinidin contribute differently to this interaction. The largest helix, Al, opposes the PT through the effect of its helix dipole. The charged residues (i.e. elements of primary structure) in helix A3 favor the PT, and mask the effect of its helix dipole (i.e. from its secondary structure) which opposes the transfer. Steric effects in the activation process were evaluated by using the indole of Trp 184 which is oriented over the hydrogen bonded system of Asn 182 and His 162. Steric hindrance in the protein restricts the orientation that ligands could assume above this hydrogen bonded system. The orientation favored by actindin was close to the one that allowed 5-HT to activate the model receptor through a PT. In this orientation other congeners of tryptamine also lower the barrier and increase the driving energy for PT with a rank order that appears to correlate with the intrinsic efficacies of the drugs, as expected from receptor theory. The heuristic model for the activation of a 5-HT receptor suggests that ligands overcome the electrostatic effects from the receptor structure that stabilize the "inactivated" form of the receptor while the steric effects in the binding pocket can select the proper orientation for the ligand so that activation can occur.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
