Please use this identifier to cite or link to this item:
http://hdl.handle.net/10603/4694
Title: | X-ray crystallographic studies on HIV-1 protease |
Researcher: | Das, Amit |
Guide(s): | Hosur, M V |
Keywords: | crystal structure HIV-1 protease enzyme catalysis mechanism drug resistance substrate RT-RH TFR-PR tetrahedral intermediate |
Upload Date: | 13-Sep-2012 |
University: | Homi Bhabha National Institute |
Completed Date: | 09-03-2012 |
Abstract: | The unique contribution of the candidate is structural mapping of the peptide bond cleavage reaction catalyzed by HIV-1 protease (HIV-1 PR). The candidate has obtained the first crystal structures of complexes between an active HIV-1 PR enzyme and natural type-1 and type-2 substrates. In the complexes with a type-2 substrate, the substrate is captured in the active site at three different stages of the cleavage reaction: when bound as a regular peptide, after in-situ modification into a tetrahedral reaction intermediate, and when cleaved into product peptides, which are still bound in the active site of the enzyme. He has discovered an inter-enzyme-substrate short ionic hydrogen bond (SIHB) in the tetrahedral intermediate complex, and an intra- enzyme low barrier hydrogen bond (LBHB) just after the substrate is cleaved into product peptides. In the complex with type-1 substrate, the substrate is cleaved and the C-terminal peptide bond about the proline residue displays cis conformation. These are very novel and atomic level descriptions of substrate recognition and processing by HIV-1 protease enzyme. Based on these structural inputs he has given a detailed mechanism of the peptide bond hydrolysis by HIV-1 PR. Through very high resolution structures, the candidate has found that in unliganded HIV-1 PR, the inter-aspartate hydrogen bond is not a LBHB, in contradiction to the latest mechanistic proposal. Further, the candidate has found novel arrangement of water molecules at the catalytic centre, only when the pH is non-optimal for enzyme activity. The rate reduction at non-optimal pH?s is suggested to be partly due to this water structure. The candidate has also determined the structures of the complexes of FDA approved drug, ritonavir with native as well as HIV-1 PR mutants that are resistant to ritonavir. These structures reveal that, in V82F mutant, loss of hydrophobic interactions contributes significantly toward development of resistance and the M36I mutant has a compensatory role in restoring viral fitness. |
Pagination: | 231p. |
URI: | http://hdl.handle.net/10603/4694 |
Appears in Departments: | Department of Chemical Sciences |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
01_title.pdf | Attached File | 1.7 MB | Adobe PDF | View/Open |
02_certificate.pdf | 414.55 kB | Adobe PDF | View/Open | |
03_declaration.pdf | 649.13 kB | Adobe PDF | View/Open | |
04_dedication.pdf | 359.25 kB | Adobe PDF | View/Open | |
05_acknowledgements.pdf | 318.72 kB | Adobe PDF | View/Open | |
06_contents.pdf | 359.33 kB | Adobe PDF | View/Open | |
07_synopsis.pdf | 579.95 kB | Adobe PDF | View/Open | |
08_list of figures.pdf | 298.95 kB | Adobe PDF | View/Open | |
09_list of tables.pdf | 194.02 kB | Adobe PDF | View/Open | |
10_chapter 1.pdf | 889.1 kB | Adobe PDF | View/Open | |
11_chapter 2.pdf | 1.17 MB | Adobe PDF | View/Open | |
12_chapter 3.pdf | 4.22 MB | Adobe PDF | View/Open | |
13_chapter 4.pdf | 2.09 MB | Adobe PDF | View/Open | |
14_chapter 5.pdf | 2.15 MB | Adobe PDF | View/Open | |
15_chapter 6.pdf | 3.4 MB | Adobe PDF | View/Open | |
16_references.pdf | 928.81 kB | Adobe PDF | View/Open | |
17_key words and abbreviations.pdf | 257.91 kB | Adobe PDF | View/Open | |
18_abstract.pdf | 81.96 kB | Adobe PDF | View/Open | |
19_list of publications.pdf | 314.77 kB | Adobe PDF | View/Open |
Items in Shodhganga are licensed under Creative Commons Licence Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0).
Altmetric Badge: