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STRUCTURE-FUNCTION STUDIES ON THE MAMMALIAN INTESTINAL DIPEPTIDE TRANSPORTER hPEPT1 by Liya Xu ________________________________________________________________ A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (NEUROSCIENCE) August 2010 Copyright 2010 Liya Xu
|Title||Structure-function studies on the mammalian intestinal dipeptide transporter hPEPT1|
|Author email@example.com; firstname.lastname@example.org|
|Degree||Doctor of Philosophy|
|School||College of Letters, Arts and Sciences|
|Advisor (committee chair)||
Alkana, Ronald L.
Davies, Daryl L.
|Advisor (committee member)||
Haworth, Ian S.
Farley, Robert A.
|Abstract||Intestinal protein digestion generates a massive variety and quantity of short chain peptides that are later absorbed into small intestinal epithelial cells by the di/tri-peptide transporter (PEPT1) on the apical membrane of enterocytes. PEPT1 functions as an electrogenic proton/peptide symporter with the ability to transport most di- and tripeptide arising from food digestion. It also has significance in its ability to transport pharmacologically active drugs. Due to its uniquely broad substrate specificity and high capacity, hPEPT1 has been suggested to be relevant drug targets at the level of drug transport. Substrate docking studies to identify specific interactions between the substrate and transporter would be facilitated by crystallization of hPEPT1; however, crystallization of hPEPT1 protein is currently unapproachable due to the size of the protein and the requirement of a lipid membrane to retain tertiary. My research built on the rudimentary computer model of hPEPT1 generated by Dr. Michael Bolger. The specific Aims of this dissertation consist of two parts: 1) to obtain structural information about the transport with a focus on TMD10 and loop 6-7; 2) to investigate the effect of ethanol on hPepT1 transport function. This was accomplished by 1) testing the hypothesis that physical-chemical parameters in TMD10 and Loop6~7 region in hPepT1 play an important role in translocation 2) the hypothesis that endotoxin LPS inhibit hPEPT1 transport function.; This work will contribute to our long-term goal of validating and developing a refined, experimentally constrained computer model of hPEPT1 that can be used as template for rational drug design and identify new targets and treatment strategies that can be used to improve the dietary as well as immunological deficiencies that are experienced by the alcoholic patient.|
|Keyword||hPEPT1; structure-function study; dipeptide transporter; membrane protein; computer modeling|
|Part of collection||University of Southern California dissertations and theses|
|Publisher (of the original version)||University of Southern California|
|Place of publication (of the original version)||Los Angeles, California|
|Publisher (of the digital version)||University of Southern California. Libraries|
|Provenance||Electronically uploaded by the author|
|Legacy record ID||usctheses-m3307|
|Repository name||Libraries, University of Southern California|
|Repository address||Los Angeles, California|
|Full text||STRUCTURE-FUNCTION STUDIES ON THE MAMMALIAN INTESTINAL DIPEPTIDE TRANSPORTER hPEPT1 by Liya Xu ________________________________________________________________ A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (NEUROSCIENCE) August 2010 Copyright 2010 Liya Xu|