利用核磁共振光譜研究可用於阻斷S100A9 與RAGE V Domain 交互作用及S100A4與p53蛋白質相互作用的拮抗劑

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研究生：	凱瑞森 Katte, Revansiddha
論文名稱：	利用核磁共振光譜研究可用於阻斷S100A9 與RAGE V Domain 交互作用及S100A4與p53蛋白質相互作用的拮抗劑 NMR study for Identifying Inhibitor amongst S100A9 - RAGE V domain and S100A4 - p53 proteins interactions
指導教授：	余靖 Yu, Chin
口試委員:	蘇士哲 Su, Shih-Che 莊偉哲 Chuang, Woei-Jer 陳金榜 Chen, Chin-Pan 鄒瑞煌 Chou, Ruey-Hwang
學位類別：	博士 Doctor
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2020
畢業學年度：	108
語文別：	英文
論文頁數：	150
中文關鍵詞：	利用核
外文關鍵詞：	S100A4 - p53 proteins interactions
相關次數：	點閱：3 下載：0
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根據研究顯示，身為顯著多功能蛋白質家族的S100蛋白會參與調節數個重要的生物途徑；然而，所有S100蛋白成員的活性都取決於其細胞特異性的表達模式和鍵結目標。S100蛋白透過和RAGE受體的交互作用來觸發發炎反應，並啟動信號級聯和以NF-κB依賴性方式調節發炎反應、細胞增殖、細胞分化及腫瘤發展。此外亦有證據指出，多種S100蛋白透過和p53蛋白結合並抑制其抑制腫瘤的活性來參與腫瘤性疾病。因此，對於定義S100蛋白與目標蛋白交互作用的差異行為之蛋白特異性的基礎，我們依然不了解。尤其是在S100蛋白質複合物之間相互作用弱的情況下，對形成的大分子複合物的結構見解將對藥物研究產生直接影響，以識別和選擇潛在的目標。為了回答這些重要問題，我們選擇屬於S100蛋白家族的S100A12、S100A9、S100A4和p53蛋白作為研究工作的目標。
在第二章中，S100A9和S100A12皆與人類S100鈣結合蛋白家族相關，而其EF-hand的位置與鈣離子結合後將會促進其與目標蛋白的交互作用，並改變其構型。RAGE(Receptor for Advanced Glycation End products)中的V domain對於和S100A9的結合至關重要，其和S100蛋白家族的結合亦有助於細胞增殖。在本論文中，我們證明了S100A12蛋白會阻礙S100A9與RAGE V domain的結合。我們使用螢光和NMR光譜來分析S100A9與S100A12的交互作用，並以1H-15N HSQC滴定及HADDOCK程序所獲得的數據建立S100A9-S100A12二元複合體，而後將該複合體和S100A9與RAGE V domain以相同方向疊合。結果顯示S100A12蛋白可阻斷S100A9與RAGE V domain之間的交互作用，也意味著S100A12可作為S100A9和RAGE V domain相互作用的拮抗劑。這項結果對於開發以S100家族蛋白為基礎的抗癌藥物來說相當有利。
在第三章中，在數種腫瘤形式中過度表達的S100A4是一種小型鈣離子結合蛋白，其與轉移相關之特性使得他在癌症轉移中起著相當重要的作用。根據先前的研究指出，腫瘤抑制因子p53是S100A4的主要目標之一，透過p53，S100A4可調節膠原蛋白的表達和細胞增殖；且當S100A4與p53相互作用時，其能破壞野生型p53的穩定性。在當前的研究中，透過H-15N HSQC滴定及HADDOCK程序所獲得的結果可知，在有鈣離子的情況下，S100A4會與p53的非穩定TAD (transactivation domain)段和pentamidine分子作用。根據我們的結果亦得知p53的TAD段和pentamidine分子在S100A4上的結合位置相近，該發現表示其競爭性的結合機構可干擾S100A4和p53的結合，並增加p53的水平。此外，利用MCF 7細胞的WST-1測試，我們比較了p53活性的不同方面，並發現當pentamidine分子存在時，p53的活性就會提高，也導致其細胞增殖降低。總體而言，我們的研究指出，干擾S100A4和p53的交互作用可阻止癌症的進程；也就是說，S100A4-p53抑制劑可作為癌症治療的新途徑之一。
綜上所述，我們證明了蛋白質-蛋白質和蛋白質-藥物的交互作用對於理解尚未明白的相互作用相當重要，且其亦可用於針對細胞增殖相關疾病（如癌症）治療方法的設計。

Evidence strongly supports that S100 proteins, as a remarkable multifunctional protein family, are involved in the regulation of several important biological processes. However, the activities of all members S100 proteins depend on the cell-specific expression patterns and binding targets. S100 proteins trigger inflammation through interacting with receptors RAGE and initiates a signaling cascade and regulates inflammation, cell proliferation, differentiation, and tumor development in an NF-κB-dependent manner. Additionally, multiple S100 proteins have been shown to participate in neoplastic disorders by binding to p53 and inhibits cancer-suppressing activity. Therefore, the basis of S100 protein specificity which defines the differential behavior of interaction with its target proteins still remains unclear. The structural insights into the macromolecular complexes formed, especially in the case of weak interaction between S100 protein-protein complexes will have direct ramifications in pharmaceutical research to identify and select the potential targets. To answer these important questions, we selected S100A12, S100A9, and S100A4 proteins belonging to the S100 protein family and p53 as the proteins of interest for my research work.
In chapter II, the proteins S100A9 and S100A12 are associated with the human S100 calcium-binding protein family. These proteins promote interaction with target proteins and alter their conformation when they bind to calcium ions in EF-hand motifs. The V domain of RAGE (Receptor for Advanced Glycation End products) is crucial for S100A9 binding. The binding of RAGE with S100 family proteins aids in cell proliferation. In this report, we demonstrate that S100A12 protein hinders the binding of S100A9 with the RAGE V-domain. We used fluorescence and NMR spectroscopy to analyze the interaction of S100A9 with S100A12. The binary complex models of S100A9-S100A12 were developed using data obtained from 1H-15N HSQC NMR titrations and the HADDOCK (High Ambiguity Ariven Biomolecular Docking) program. We overlaid the complex models of S100A9-S100A12 with the same orientation of S100A9 and the RAGE V-domain. This complex showed that S100A12 protein blocks the interaction between S100A9 and the RAGE V-domain. It means S100A12 may be used as an antagonist for S100A9 and RAGE V domain interaction. The results could be favorable for developing anti-cancer drugs based on S100 family proteins.
In chapter III, Metastasis-associated S100A4 protein is a small calcium-binding protein typically overexpressed in several tumor forms, and it is widely accepted that S100A4 plays a significant role in the metastasis of cancer. Tumor suppressor p53 is one of the S100A4’s main targets. Previous reports show that through p53, S100A4 regulates collagen expression and cell proliferation. When S100A4 interacts with p53, the S100A4 destabilizes wild type p53. In the current study, based on 1H-15N HSQC NMR experiments and HADDOCK results, S100A4 interacts with the intrinsically unstructured transactivation domain (TAD) of the protein p53 and the pentamidine molecules in the presence of calcium ions. Our results suggest that the p53 TAD and pentamidine molecules share similar binding sites on the S100A4 protein. This observation indicates that a competitive binding mechanism can interfere with the binding of S100A4-p53 and increase the level of p53. Also, we compare different aspects of p53 activity in the WST-1 test using MCF 7 cells. We found that the presence of a pentamidine molecule results in higher p53 activity, which is also reflected in less cell proliferation. Collectively, our results indicate that disrupting the S100A4-p53 interaction would prevent cancer progression, and thus S100A4-p53 inhibitors provide a new avenue for cancer therapy.
In conclusion, we demonstrated that the protein-protein and protein-drug interactions are of much importance for understanding the unclear interactions for the design of new therapies to treat diseases associated with the cell proliferation such as cancer.

Table of Contents
Abstract in Chinese.……………………………………………………I
Abstract in English …………………………………………………III
Acknowledgment …………………………………………………………V
Abbreviations…………………………………………………………VII
Table of Contents……………………………………………………IX
List of figures………………………………………………………XIII
List of tables………………………………………………………XXIII
Chapter I
Introduction Part-I: The biological background of the study
1.1.    Introduction………………………………………………………………2
1.2.    Protein transport……………………………………………………5
1.3.    Protein…………………………………………………………………8
1.3.1. Building blocks of protein: Amino acids………………9
1.3.2. Protein structures…………………………………………11
1.4.    S100 Proteins…………………………………………………………14
1.5.    Receptor for advanced glycation end product (RAGE)………19
1.6.    Introduction of p53 protein………………………………………22
1.7.    S100 protein interaction with p53 protein……………………28
Part-II: Protein sample Prepare and Protein-Ligand Interactions
1.8.    Protein sample preparation………………………………………31
1.9.    Structure determination……………………………………………32
1.10.    Distance restraints for structure calculation………………33
1.11.    Protein-Ligand interaction………………………………………33
1.11.1. NMR spectroscopic analysis of protein-ligand binding……………………34
1.11.2. Fluorescence spectroscopic analysis of Protein-Ligand interactions…………35
1.11.3. Isothermal titration calorimetric (ITC) studies on protein-ligand interaction…36

Chapter II
Blocking the interaction between S100A9 protein and the RAGE V domain using S100A12 protein

2.1.    Introduction………………………………………………………41
2.1.1. S100A9 Protein……………………………………………………42
2.1.2. RAGE Protein………………………………………………………45
2.1.3. S100A12 protein…………………………………………………46
2.1.4. The objective of the research………………………………48
2.2.    Materials and Methods…………………………………………48
2.2.1. Materials…………………………………………………………48
2.2.2. Expression and purification S100A12 protein……………49
2.2.3. Expression and Purification S100A9 protein………………54
2.2.4. 2D 1H-15N HSQC NMR titration experiments…………………59
2.2.5. Molecular docking studies.............................60
2.2.6. Fluorescence experiments for binding affinity (Kd)……61
2.3.    Results and Discussion………………………………………62
2.3.1 The binding interface of S100A9 and the S100A12…………62
2.3.2. Docking studies…………………………………………………66
2.3.3. Binding constant measurements………………………………68
2.3.4. S100A12 inhibits the S100A9-RAGE V-domain complex………70
2.4.    Conclusion and future perspectives…………………………71

Chapter III
Pentamidine inhibit S100A4 - p53 interaction and decreases cell proliferation activity
3.1.    Introduction.........................................74
3.1.1. p53 Protein………………………………………………………74
3.1.2. S100 Protein………………………………………………………75
3.1.3. S100A4 Protein……………………………………………………75
3.1.4. Pentamidine drug molecule………………………………………77
3.1.5. Objectives of the research……………………………………77
3.2.    Materials and Methods…………………………………………78
3.2.1. Materials……………………………………………………………78
3.2.2. Expression and Purification of p53 Protein………………79
3.2.3. Expression and Purification of S100A4 Protein……………87
3.2.4. NMR Titration Experiments……………………………………93
3.2.5. Molecular docking of S100A4 with p53TAD and pentamidine……96
3.2.6. Cell proliferation assay…………………………………………97
3.3.    Results and discussion……………………………………………98
3.3.1 The binding interface between S100A4 and p53TAD……………98
3.3.2. Mapping the pentamidine drugs binding interface to S100A4…105
3.3.3. Comparison of S100A4/p53TAD and S100A4/pentamidine complexes………110
3.3.4. WST-1 cell proliferation assay……………………………113
3.4.    Conclusion and future perspectives………………………116
References……………………………………………………………………118














List of Figures
Chapter – I

Figure 1.1. Anatomy of the Eukaryotic cell and Prokaryotic cell………………………………3
Figure 1.2. An illustration showing the flow of information between DNA, RNA, and protein…5
Figure 1.3. Secretion pathways of the protein synthesized in the human cell…………………….6
Figure 1.4. The structure of general amino acid………………………10
Figure 1.5. Amino acids linking via a peptide bond…………………11
Figure 1.6. A representation of the primary protein structure……………………………………12
Figure 1.7. A representation of the alpha-helix and beta-sheet of secondary protein structure with hydrogen bonding…………………13
Figure 1.8. A representation of the Tertiary and Quaternary protein structure………………14
Figure 1.9. Dimer structure of S100 proteins. S100 proteins are characterized as calcium-binding EF-hand motifs and They exist as homo and heterodimers. Each monomer consists of two EF-hands connected by a hinge region……………………………………………16
Figure 1.10. During various stages of tumorigenic processes, S100 proteins may have important roles. S100 proteins are involved in many aspects of cancer's phenotypic characteristics including cell differentiation regulation, cell cycle progression, cell proliferation, cell apoptosis, cell motility, tumor microenvironment, and cancer stem cells, etc…………………………………...18
Figure 1.11. Some S100 proteins that interact with RAGE, thereby activating the signaling pathways for MAPK, PI-3K-AKT, and NF-kB, leading to the up-regulation of genes involved in cell survival and proliferation. In other cases, the apoptosis cascade is triggered by JNK and caspases activation……………………………………………………………22
Figure 1.12. Schematic diagrams showing the domain structure of tumor suppressor p53 consists. An intrinsically unfolded N-terminal transactivation domains TAD, a proline-rich domain (PRD), a DNA-binding domain (DBD), a tetramerization domain (TET), and a regulatory domain (REG). whereas intrinsically unfolded N-terminal transactivation domains TAD having two sun-domains, TAD1 and TAD2……………………………………………25
Figure 1.13. Complexes of the p53 fragments derived from its N-terminal region bound to different partners. (A) Complex with the N-terminal domain of the p53TAD with transcriptional adapter zinc finger domains (TAZ1) of CBP (PDB code 5HOU). (B) p53TAD with TAZ2 of CBP (PDB code 5HPD). (C) Solution structure of the p53 TAD with NCBD………………27

Chapter – II

Figure 2.1. Homodimeric calcium bound cartoon diagram of S100A9 from protein data bank file 1IRJ. A subunit with the EF hand-marked is shown in green……………………………………43
Figure 2.2. Human S100A12 protein clone construct. (A) The map of the 21b (+) vector. (B) The sequence of the multiple cloning sites where the human S100A12 protein sequence was inserted at the Ndel and Xhol restriction sites. (C) The amino acid sequence of the human S100A12 protein. Amino acids are denoted in single letter code……………………………………………………49

Figure 2.3. (A) The chromatography profile of FPLC Q-column purification of S100A12 protein, elute was collected as E1, E2, and E3. (B) 15% SDS-PAGE analysis of Q-column elution fractions of S100A12 protein, the major band appeared near 10 KDa…………………………………51
Figure 2.4. (A) The chromatography profile of FPLC HIC-column purification of S100A12 protein, elute was collected as E1 and E2. (B) 15% SDS-PAGE analysis of HIC-column elution fractions of S100A12 protein, the major band appeared near 10 KDa………………………52
Figure 2.5. (A) The chromatography profile of HPLC purification of S100A12 protein, elute was collected as E1 and E2. (B) 15% SDS-PAGE analysis of HPLC elution fractions of S100A12 protein, the major band appeared near 10 KDa. (C) Electrospray ionization mass spectrometry (ESI-MS) results confirm the molecular weight of purified S100A12……………………………53
Figure 2.6. Human S100A9 protein clone construct. (A) The map of the 21b (+) vector. (B) The sequence of the multiple cloning sites where the human S100A9 protein sequence was inserted at the Ndel and Xhol restriction sites. (C) The amino acid sequence of the human S100A9 protein. Amino acids are denoted in single letter code……………………………………………………54
Figure 2.7. (A) The chromatography profile of FPLC Q-column purification of S100A9 protein, elute was collected as E1, E2, and E3. (B) 15% SDS-PAGE analysis of Q-column elution fractions of S100A9 protein, the major band appeared near 13 KDa……………………57
Figure 2.8. (A) The chromatography profile of FPLC HIC-column purification of S100A9 protein, elute was collected as E1 and E2. (B) 15% SDS-PAGE analysis of HIC-column elution fractions of S100A9 protein, the major band appeared ̴ 13 KDa……………………………57

Figure 2.9. (A) The chromatography profile of HPLC purification of S100A9 protein, elute was collected as E1 and E2. (B) 15% SDS-PAGE analysis of HPLC elution fractions of S100A9 protein, the major band appeared near 13 KDa. (C) Electrospray ionization mass spectrometry (ESI-MS) results confirm the molecular weight of purified S100A9……………………………58
Figure 2.10. (A). Superimposed HSQC spectra of 1.01 mM S100A9 (15N-labeled) with those of S100A12 at molar ratios of 1:0 (blue) and 1:1 (red). The residues are shown in a black box were recognized using bar diagrams. (B). Bar diagram analysis of chemical shift (1H and 15N) perturbations of the amino acid residues in S100A12 upon complex formation with the S100A9. The threshold of selected residues exhibiting a significant change is represented by a violet line (>0.023). (C). Bar diagram analysis of changes in cross-peak intensity ratio (I/I0). I represent the intensity of the S100A9–S100A12 complex, and I0 is the intensity of free S100A12. The violet line shows the threshold of selected residues that display a notably reduced intensity (<0.26). (D). Selected residues of S100A9 labeled in red on the three-dimensional structure of the heterodimer complex of S100A9 (green) and S100A12 (blue)………………………………………63
Figure 2.11. (A). Superimposed HSQC spectra of 0.98 mM S100A12 (15N-labeled) with those of S100A9 at molar ratios of 1:0 (blue) and 1:1 (red). These residues are shown in the black box were recognized using bar diagrams.  (B). Bar diagram analysis of chemical shift (1H and 15N) perturbations of the amino acid residues in S100A9 upon complex formation with the S100A12. The threshold of selected residues exhibiting significant changes was represented by a violet line (>0.017). (C). Bar diagram analysis of changes in cross-peak intensity ratio (I/I0). I represent the intensity of the S100A12–S100A9 complex, and I0 is the intensity of free S100A12. The violet line shows the threshold of selected residues that display a notably reduced intensity (<0.29).  (D). Selected residues of S100A12 labeled in red on the three-dimensional structure of the heterodimer complex of S100A12 (blue) and S100A9 (green)………………………………………65
Figure 2.12. HADDOCK results shown as the binding site between S100A12 and S100A9 with side chains of selected residues. The stick structures of residues Asn-13, Ile-14, Tyr-18, Thr-38, and Glu-40 of S100A12 (blue) and residues Phe-48, Lys-50, Lys-51, Glu-56, Ile-59, Agr-85, and Leu-86 of the S100A9 (green) are shown in red……………67
Figure 2.13. Ramachandran plot statistics of the complex S100A9 with S100A12 using PROCHECK analysis. About 84% of the residues are in the favored region and the disallow region is 0.5%. The overall average of the G-factor is -0.2, which is in the usual region……………68
Figure 2.14. (A). Emission spectra of 2 µM S100A9 fluorescence titrations exhibiting decreased fluorescence intensities with an increasing concentration of S100A12 at the micromolar level. (B). The nonlinear curve of fluorescence intensity changes versus S100A12 concentration at a wavelength of 345 nm. Kd was calculated as 1.3±0.36 µM using equation 1…………………69
Figure 2.15. Superimposition of two complex structures (S100A9-RAGE and S100A9-S100A12). The S100A9-RAGE V-domain complex is shown in red and cyan, while the S100A9-S100A12 complex is shown in green and blue, respectively. The S100A12 protein clearly inhibits the binding between S100A9 and the RAGE V domain……………………………70




Chapter – III

Figure 3.1. p53TAD (1-73) protein clone construct. (A) The map of the 28a (+) vector. (B) The sequence of the multiple cloning sites where the p53TAD protein sequence was inserted at the Ndel and Xhol restriction sites. (C) The amino acid sequence of the p53TAD protein with His-tag. Amino acids are denoted in single letter code. (D) The amino acid sequence of the p53TAD protein after enzyme cleavage……………………………………………………………………………79
Figure 3.2. Terminal structure of Ni2+-NTA Sepharose. The binding interactions between two consecutive histidine residues in the (His)6 – tag and Ni-NTA matrix for the purification of recombinant proteins………………………………82
Figure 3.3. Ni2+-NTA affinity column purification of the recombined (His)6 - p53 TAD (1-73) fusion protein and 15% SDS-PAGE analysis. The impurities were removed in the flow through (F1, F2 & F3) and washing steps (W1 to lane W2). The fusion protein is eluted in the pure form with 500 mM imidazole (E1, E2, and E3) ………………………………83
Figure 3.4. (A) The chromatography profile of FPLC SEC-column purification of the recombined (His)6 - p53 TAD (1-73) fusion protein, elute was collected as E1 to E6. (B) 15% SDS-PAGE analysis of SEC-column elution fractions of recombined (His)6 - p53 TAD (1-73) fusion protein, the major band appeared near 18 KDa……………………83
Figure 3.5. (A) The chromatography profile of FPLC SEC-column purification of the p53 TAD (1-73) after enzyme cleavage, elute was collected as E1 to E2. (B) 15% SDS-PAGE analysis of SEC-column elution fractions of p53 TAD (1-73) fusion protein……………………84

Figure 3.6. (A) The chromatography profile of HPLC purification of recombined (His)6 - p53 TAD (1-73) fusion protein, elute was collected as E1. (B) 15% SDS-PAGE analysis of HPLC elution fractions of recombined (His)6 - p53 TAD (1-73) fusion protein. (C) Electrospray ionization mass spectrometry (ESI-MS) results confirm the molecular weight of purified recombined (His)6 - p53 TAD (1-73) fusion protein………………………………………………………85
Figure 3.7. (A) The chromatography profile of HPLC purification of p53TAD (1-73) protein (after thrombin cleavage), elute was collected as E1. (B) 15% SDS-PAGE analysis of HPLC elution fractions of p53TAD (1-73) protein (after thrombin cleavage). (C) Electrospray ionization mass spectrometry (ESI-MS) results confirm the molecular weight of purified p53TAD (1-73) protein (after thrombin cleavage) …………86
Figure 3.8. Human S100A4 protein clone construct. (A) The map of the 21b (+) vector. (B) The sequence of the multiple cloning sites where the human S100A4 protein sequence was inserted at the Ndel and Xhol restriction sites. (C) The amino acid sequence of the human S100A4 protein. Amino acids are denoted in single letter code……………………………………………………89
Figure 3.9. (A) The chromatography profile of FPLC HIC-column purification of S100A4 protein, elute was collected as E1. (B) 15% SDS-PAGE analysis of HIC-column elution fractions of S100A4 protein, the major band appeared near 10 KDa…………………………90
Figure 3.10. (A) The chromatography profile of FPLC SEC-column purification of S100A4 protein, elute was collected as E1 to E9. (B) 15% SDS-PAGE analysis of SEC-column elution fractions of S100A4 protein, the major band appeared near 10 KDa………………………91
Figure 3.11. (A) The chromatography profile of HPLC purification of S100A4 protein, elute was collected as E1 and E2. (B) 15% SDS-PAGE analysis of HPLC elution fractions of S100A4 protein, the major band appeared near 10 KDa. (C) Electrospray ionization mass spectrometry (ESI-MS) results confirm the molecular weight of purified S100A4…………………92
Figure 3.12. Overlays of the 15N-1H HSQC spectra of free 0.3 mM [15N] p53(1–73) in complex with different concentrations of S100A4 proteins. in the presence of 1:0.2 (gold), 1:0.4 (green), 1:0.6 (cyan), 1:0.8 (purple), and 1:1 (blue) are shown……………………………………………93
Figure 3.13. Overlays of the 15N-1H HSQC spectra of free 0.3 mM [15N] S100A4 in complex with different concentrations of p53(1–73) proteins. in the presence of 1:0.25 (gold), 1:0.50 (green), 1:0.75 (cyan), and 1:1 (blue) are shown………………………………94
Figure 3.14. Overlays of the 15N-1H HSQC spectra of free 0.3 mM [15N] S100A4 in complex with different concentrations of the pentamidine drug molecule. in the presence of 1:0.5 (green), 1:1 (gold), and 1:2 (blue) are shown…………………………………………………95
Figure 3.15. Binding of S100A4 with p53 TAD analyzed by 1H-15N HSQC NMR titrations. A. The 1H-15N HSQC spectra of free S100A4 in red and the 15N S100A4 with unlabeled p53TAD (blue) at a molar ratio of 1:1. Cross-peaks are shown by black boxes. B. Bar diagram of the weighted average of the chemical shift (1H and 15N) variations of the amino acid residues in the 15N S100A4 complex with unlabeled p53(1–73) proteins. The black broken line indicates the selected residues that exhibited a significant chemical shift perturbation (Δδ > 0.05 ppm) and the broken line was chosen arbitrarily to highlight those residues which are having significant perturbations. C. These selected cross-peak residues were labeled in red on the cartoon structure of S100A4 (cyan) using the PyMOL program……………………99
Figure 3.16. Binding of p53TAD with S100A4 analyzed by 1H-15N HSQC NMR titrations. A. The   1H-15N HSQC spectra of free p53TAD (red) and the 15N p53TAD with unlabeled S100A4 (blue). Cross-peaks are shown by black boxes. B. Bar diagram of the weighted average of the chemical shift (1H and 15N) variations of the amino acid residues in the 15N p53(1-73) complex with unlabeled S100A4 protein. The black broken line indicates the selected residues that exhibited a significant chemical shift perturbation (Δδ > 0.03 ppm) and the broken line was chosen arbitrarily to highlight those residues which are having significant perturbations……………………103
Figure 3.17. The dissociation constant (Kd) calculated by the designated residues detected in 15N S100A4 HSQC titrations with p53TAD and the overall average Kd is 22 ±5 μM…………105
Figure 3.18. Binding of S100A4 with pentamidine analyzed by 1H-15N HSQC NMR titrations. A. The structural formula of pentamidine B. The 1H-15N HSQC spectra of free S100A4 (red) and the 15N labeled S100A4 with unlabeled pentamidine drug (blue). Cross-peaks perturbed are shown by black boxes. C. Bar diagram of the weighted average of the chemical shift (1H and 15N) variations of the amino acid residues in the 15N S100A4 complex with unlabeled pentamidine drug molecule. The black broken line indicates the selected residues that exhibited a significant chemical shift perturbation (Δδ > 0.04 ppm) and the broken line was chosen arbitrarily to highlight those residues which are having significant perturbations. D. These selected cross-peak residues were labeled in blue on the cartoon structure of S100A4 (cyan) using the PyMOL program……106
Figure 3.19.  The dissociation constant (Kd) calculated by the designated residues detected in 15N S100A4 HSQC titrations with pentamidine and the overall average Kd is 38 ± 9 μM………….109
Figure 3.20. The 1H-15N HSQC spectra of 15N p53TAD with unlabeled pentamidine (green). and the unlabeled pentamidine in 15N p53 TAD / unlabeled S100A4 complex mixture (yellow) at 1:1:1 ratio…………………………………………………………………110
Figure 3.21. Superimposition of two complex structures (S100A4-p53TAD1 (amino acid 17-29) and S100A4-Pentamine drug). (A). The S100A4-p53TAD1 complex is shown in cyan and green, and (B) the S100A4-pentamidine drug complex is shown in cyan and blue. (C) The overlapped structures of (A) and (B). In this overlapped figure, the pentamidine drug molecule clearly inhibits the binding between S100A4 and the p53TAD1………………………………………111
Figure 3.22. Ten overlapping water refinement structures of S100A4- p53TAD (amino acid 17–29) complexes…………………………………………………………………112
Figure 3.23. Ten overlapping water refinement structures of S100A4- pentamidine complexes……………………………………………………113
Figure 3.24. (A) Bar diagram of WST-1 assay analysis.  The height of the red and blue bars represents the ratio of cell proliferation compared with the control. The control (lane 1) is in the serum-free condition without the drug. The addition of pentamidine (5 μM) decreases the viable cell count and cell proliferation (lane 2). Pentamidine (10 μM lane 3, 20 μM lane 4, 50 μM lane 5, and 100 μM lane 6) was added gradually to the MCF7 cell cultures. The values are the average of three replicates. (B) The effect of pentamidine on p53 activation observed through western blot analysis, Beta-actin was used as an internal control……………………………………114





List of Tables
Chapter – II

Table 2.1. List of the active and passive residues used to define the ambiguous interaction restraints for the docking of S100A9 with S100A12……………………………………………64

Chapter – III

Table 3.1. List of the active and passive residues used to define the ambiguous interaction restraints for the docking of S100A4 with p53TAD……………………………………………104
Table 3.2. List of the active and passive residues used to define the ambiguous interaction restraints for the docking of S100A4 with pentamidine…………………………………………108

                                

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