Structural and functional investigation of human chemokines and applications of human chemokines in blocking HIV-1 entry

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Title: Structural and functional investigation of human chemokines and applications of human chemokines in blocking HIV-1 entry
Author: Jin, Hongjun
Abstract: Chemokines are important mediators of leukocyte migration . Chemokines bind to G protein ?coupled receptors (GPCR ) and cause conformational changes that trigger intracellular signaling pathways involved in inflammation , injury healing , cancer , metastasis , and HIV infections . No direct structural information about any chemokine receptor is available , but the structure of chemokines has been well studied . Structural studies of chemokines coupled with cell -biological investigations may lead to a better understanding of the mechanisms of chemokine -receptor interactions . In this Ph .D . project , I studied the structural and functional relationship between chemokines and chemokine receptors using NMR , X -ray crystallography , and mutagenesis approaches , coupled with several different cell -biology assays . We found that the conserved ?chemokine fold ? can support different dimerization types in the chemokines family , although changing the dimers from CC - to CXC -type fold is not readily accomplished . I also used an engineered covalently -bound dimer of the MIP -1 ? mutant , MIP -1 ? -A10C , to study the relationship between dimerization of chemokines and their interaction with the CCR5 receptor . My results suggest that MIP -1 ? dimer neither bind nor activate the CCR5 receptor . I also studied the biophysical properties of one N -terminal awkward mutant of P2 -RANTES , which was originally selected by others from a phage display using CCR5 -expressing cells . Although the NMR and X -ray crystal studies revealed that the wild type RANTES is a tight homodimer , analytical ultracentrifugation reveals that P2 -RANTES is a monomer in solution , the 1 .7 ? resolution X -ray crystal structure of P2 -RANTES was found to be a packed tetramer . The mutated N -terminal residues play a very important role in the tetramerization in the X -ray crystal structure . Finally I used the HIV -1 env mediated cell -cell fusion assay to study the combination of chemokines or chemokine variants with anti -HIV peptides C37 or /and T -20 . A surprisingly synergistic effect was found between P2 -RANTES and C37 or T -20 . This combination stratagem may lead to further useful drug combinations or drug delivery for more potent anti -HIV treatments .
URI: http : / /hdl .handle .net /1969 .1 /ETD -TAMU -2430
Date: 2009-05-15

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Structural and functional investigation of human chemokines and applications of human chemokines in blocking HIV-1 entry. Available electronically from http : / /hdl .handle .net /1969 .1 /ETD -TAMU -2430 .

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