Theses and Dissertations - UTRGV

Date of Award

5-2020

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Dr. Evangelia Kotsikorou

Second Advisor

Dr. Frank Dean

Third Advisor

Dr. Shizue Mito

Abstract

An in-house homology model of the GPR119 receptor was used to identify residues which may affect ligand binding and ligand-dependent activity through computational and experimental studies. In a docking study comparing an agonist and its inverse agonist structural analog, Leu5.43169, L6.52242 and Ser1.324 appear to be involved in ligand binding. These residues were mutated experimentally to test the predictions of the homology model. The in vitro studies indicate that Leu5.43169 and Ser1.324 mutations cause ten-fold and six-fold decreases in ligand-induced cAMP formation, indicating their importance in ligand-induced activation. Leu6.52242 mutations show minimal effect in cAMP production, indicating a lesser involvement in ligand binding. MD simulations of the homology model bound to an agonist indicate that Leu5.43169 has an indirect effect in ligand binding, via interactions with Phe6.51241, whereas Leu6.52242 is not facing the binding pocket. Ser1.324 seems to interact occasionally with the ligand headgroup.

Comments

Copyright 2020 Matthew Dy Rosales. All Rights Reserved.

https://go.openathens.net/redirector/utrgv.edu?url=https://www.proquest.com/dissertations-theses/elucidating-binding-pockect-gpr119-receptor-type/docview/2425916317/se-2?accountid=7119

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