repository
Structural Mechanics of the Host Immune System Modulation by HPV-E6 Protein and Opioids
- Author(s)
- SHAH MASAUD
- Advisor
- Sangdun Choi
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2018-02
- Language
- eng
- Keyword
- Thesis
- Alternative Abstract
- In the course of viral infection, host-immune-system play a vital role in combat and clears the pathogenic particles. The human body has been endowed with both virus-specific and non-specific strategies for this process. Interferon regulatory factors, including IRF3, play a crucial role in interferon induction after/during viral infection. In response to viral threat, activated kinases phosphorylate the autoinhibitory domain of IRF3, thereby inducing type1 interferon release. The human papilloma virus E6 protein has been widely studied due to its implication in cervical cancer. The structural mechanism of how E6 inactivates IRF3 has not been delineated yet. Consequently, this was investigated through computational procedures. Overall, our results suggested that the first N-terminal LxxLL motif (140-LDELLG-145) of IRF3 binds within the hydrophobic pocket of E6 and preclude Ser-patch phosphorylation of IRF3 that is necessary for its activation. The protein-ligand docking and drug resistance modeling revealed that the polar patches in the ligand-binding pocket of E6, which are crucial for complex stability and ligand binding, are inconsistent among hrHPV species. Such caveats pose a risk of treatment failure owing to point mutations that might render drugs ineffective and allude to multi-drug therapy. Overall, this study reveals a novel perspective of innate immune suppression in HPV infections and suggests a plausible therapeutic intervention. In the second project, I have structurally proposed and estimated the plausible TLR-dependent opioid-mediated hyperalgesic phenomenon. Opioids, the drug of choice in pain, have been recently recognized to be involved in TLR-facilitated analgesia. Numerous studies have reported that morphine and its metabolite M3G activate TLR4 pathway, however; their exact structural mechanism is lacking. We have unveiled the binding mechanism of opioids with TLR4/MD2 complex and put forth the plausible morphine- and M3G-mediated TLR4 activation mechanism. These findings are in line with previous results and also suggest a novel insight that morphine and naloxone, but not M3G, require TLR4 for its MD2-bound complexes. Morphine interacts with MD2 near its Phe126 loop to induce the active conformation (MD2C), however; this binding is likely reversible and gains stability upon interaction with TLR4. Likewise, M3G also induces the MD2C state, with both the Phe126 loop and the H1 loop being involved in its complex stability. Naloxone, which requires TLR4 interaction for complex stability, switches the active conformation of the gating loop into inactive state (MD2O). Cumulatively, our findings suggest that ligand binding and receptor clustering occur successively in opioid-induced TLR4 signaling, and that MD2 plasticity and pocket hydrophobicity are crucial for the recognition and accommodation of ligands.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 4. Theses(Ph.D)
- Files in This Item:
- There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.
-
- License
- STATISTICS
- Total Visit :3,730,855
- Total Download :1,818
- Today View :8,514
