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Computational Approaches to Identify the Structure-Function Relationships of IκB Proteins in Toll-like Receptor Signaling
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.author | Manavalan, Balachandran | - |
| dc.date.accessioned | 2018-11-08T08:02:21Z | - |
| dc.date.available | 2018-11-08T08:02:21Z | - |
| dc.date.issued | 2011-08 | - |
| dc.identifier.other | 11809 | - |
| dc.identifier.uri | https://dspace.ajou.ac.kr/handle/2018.oak/9691 | - |
| dc.description | 학위논문(박사)아주대학교 일반대학원 :분자과학기술학과,2011. 8 | - |
| dc.description.tableofcontents | Table of contents Contents ACKNOWLEDGEMENTS 1 ABSTRACT 3 1. INTRODUCTION 5 2. TOLL-LIKE RECEPTORS MEDIATED IκB REGULATION 9 2.1 IMMUNE SYSTEM 9 2.2 TLR MEDIATED NF-κB ACTIVATION 12 2.3 STRUCTURE AND FUNCTION OF IκB PROTEINS 13 3. PROTEIN STRUCTURE PREDICTION 22 3.1 OVERVIEW 22 3.2 FOUR LEVELS OF PROTEIN STRUCTURE 22 3.3 PROTEIN STRUCTURE PREDICTION 24 3.4 MOLECULAR DOCKING 27 4. METHODS 29 4.1 MOLECULAR MODELING 29 4.2 PROTEIN MODEL QUALITY ASSESSMENT 30 4.3 DOCKING 30 4.5 MOLECULAR DYNAMIC SIMULATION 34 4.6 MODEL VISUALIZATION AND ANALYSIS 34 5. RESULTS (EXTENDED ABSTRACTS OF MANUSCRIPTS 36 5.1 PAPER 1: Molecular Modeling-based evaluation of dual functions of IκBζ ankyrin repeat domain in toll-like receptor signaling 36 5.2 PAPER 2: Structure-function relationship of cytoplasmic and nuclear IκB proteins: An in silico analysis 39 5.3 PAPER 3: Molecular modeling-based evaluation of hTLR10 and identification of potential ligands in toll-Like receptor signaling 43 5.4 PAPER 4: Molecular modeling of the reductase domain to elucidate the reaction mechanism of reduction of peptidyl thioester into its corresponding alcohol in non-ribosomal peptide synthetases 46 6. CONCLUSIONS 47 REFERENCES 49 APPENDIX 54 PAPER 1 54 PAPER 2 66 PAPER 3 83 PAPER 4 97 | - |
| dc.language.iso | eng | - |
| dc.publisher | The Graduate School, Ajou University | - |
| dc.rights | 아주대학교 논문은 저작권에 의해 보호받습니다. | - |
| dc.title | Computational Approaches to Identify the Structure-Function Relationships of IκB Proteins in Toll-like Receptor Signaling | - |
| dc.type | Thesis | - |
| dc.contributor.affiliation | 아주대학교 일반대학원 | - |
| dc.contributor.department | 일반대학원 분자과학기술학과 | - |
| dc.date.awarded | 2011. 8 | - |
| dc.description.degree | Master | - |
| dc.identifier.localId | 569603 | - |
| dc.identifier.url | http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000011809 | - |
| dc.description.alternativeAbstract | Abstract A variety of microbial components activate nuclear factor-κB (NF-κB), a transcription factor that plays an important role in both innate and adaptive immunity. Cytoplasmic IκB proteins are primary regulators that interact with NF-κB subunits in the cytoplasm of unstimulated cells. Upon stimulation, these IκB proteins are rapidly degraded, thus allowing NF-κB to translocate into the nucleus and activate the transcription of genes encoding various immune mediators. Subsequent to translocation, nuclear IκB proteins play an important role in the regulation of NF-κB transcriptional activity by acting either as activators or inhibitors. To date, molecular basis for the binding of IκBα and IκBβ along with their partners is known; however, the activation and inhibition mechanism of the remaining IκB (IκBNS, IκBε, IκBζ and Bcl-3) proteins remains elusive. Moreover, even though IκB proteins are structurally similar, it is difficult to determine the exact governing specificities of IκB proteins towards their respective binding partners. The three-dimensional structures of IκBNS, IκBζ and IκBε were modeled. Subsequently, we used an explicit solvent method to perform detailed molecular dynamic simulations of these proteins along with their known crystal structures (IκBα, IκBβ and Bcl-3). Detailed analyses of these trajectories have revealed that conformational changes takes place in loop regions (highly flexible). Furthermore, the refined models of IκBNS, IκBε, IκBζ and Bcl-3 were used for multiple protein-protein docking studies for the identification of IκBNS-p50/p50, IκBε-p50/p65, Bcl-3-p50/p50, IκBζ-p50/p65 and -p50/p50 complexes in order to study the structural basis of their activation and inhibition mechanism. The docking experiments revealed that IκBε masked the nuclear localization signal (NLS) of the p50/p65 subunits, thereby preventing its translocation into the nucleus. For the Bcl-3- and IκBNS-p50/p50 complexes, the results show that Bcl-3 mediated transcription takes place through its transactivation domain (TAD), while IκBNS inhibited transcription due to its lack of a TAD. Additionally, the opposite functions of IκBζ was revealed by our docking studies i.e., binding of IκBζ ankyrin repeats with the p50/p65 N-terminal DNA binding domain prevents NF-κB mediated transcriptional activation and IκBζ-p50/p50 dimer complex, which mediate transcriptional activation by its TAD, present at the N-terminal domain of IκBζ. These two different binding schemes of IκBζ may be responsible for its opposite function. The predicted complexes in our current study correlated well with the previous biochemical studies. Moreover, the numbers of identified flexible residues were equal in number among all IκB proteins except IκBζ. The presence of high number of flexible residues in IκBζ is responsible to mediate an interaction with different sets of nuclear protein, when compared with other IκB proteins. Finally, the identified flexible residues were not conserved among the IκB family members and this non-conservation could be the primary reason for their exhibited binding partner specificities. The current data obtained from our structural studies will be helpful for the future design of peptides that can target the NF-κB signaling for the development of novel anti-inflammatory or anti-cancer drugs. | - |
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