Structural investigation of HIV-1 GP160 and gag-pol polyprotein recognition site with HIV-1 protease
Masters Thesis
2022. Structural investigation of HIV-1 GP160 and gag-pol polyprotein recognition site with HIV-1 protease. Masters Thesis Canterbury Christ church University School of Psychology and Life Sciences
Type | Masters Thesis |
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Qualification name | MSc by Research |
Abstract | HIV (human immunodeficiency virus) is an infectious virus that if left untreated can progress into AIDS (acquired immunodeficiency syndrome) and is a devastating and lethal disease with millions of related fatalities across the globe since its discovery. The viral particle is made up of multiple mature proteins which need to be processed for it to form. Two major precursor proteins are the polyprotein gag-pol and gp160, gag-pol is cleaved by the viral enzyme HIV-1 protease into the major structural proteins and all viral enzymes used by HIV and gp160 is cleaved by the host enzyme furin creating the transmembrane/cell surface protein complex gp41/gp120 responsible for the binding to host cells. Currently there are partial crystal structure available for gp160 but missing the furin cleavage site and no full structure of gag-pol is available, with partial structures made up of its constituent proteins being accesible. This study focuses on the areas of these proteins that are cleaved to create the key proteins used by HIV. Homology models were generated for the entirety of gag-pol and gp160 using the I-Tasser webserver. The area of interest in gp160, the loop cleaved by furin and the surrounding area, was refined via loop modelling. The gag-pol structure and the loop model were then further refined using molecular dynamic simulation. The area of particular interest on gag-pol, the cleave sites, was further investigated by binding HIV-1 protease to the 4 most conserved sites. The sites were analysed, and the best binding interaction was taken into further MD to observe it over time. This study overall has produced a structure of the gp160 furin cleavage site, the first structure of gagpol in its entirety simulated for 100ns as well as information on the docking of HIV-1 protease with gag-pol and observations of the binding interactions over time. This data creates a basis for further study into the processing of HIV proteins as well as a starting point in the design of possible targeted therapies aimed at preventing the cleavage of the precursor proteins. |
Keywords | Structural investigation of HIV-1 GP160 ; Gag-pol polyprotein recognition; HIV-1 protease |
Year | 2022 |
File | File Access Level Open |
Publication process dates | |
Deposited | 12 Jul 2023 |
https://repository.canterbury.ac.uk/item/950wv/structural-investigation-of-hiv-1-gp160-and-gag-pol-polyprotein-recognition-site-with-hiv-1-protease
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