臺灣博碩士論文加值系統

中文摘要:
傳染性華氏囊病毒 (IBDV) 具高度傳染性會造成感染雛雞之永久性免疫機能抑制，其結構蛋白VP2為此病毒的主要免疫原，此蛋白會自我組裝形成一個十二面體 (dodecahedral) T=1的次病毒顆粒 (SVP) 結構，了解其結構將有助於疫苗的開發。在這項研究中，傳染性華氏囊病毒次病毒顆粒立方晶體結構被解析達2.6 Å 的解析度，於晶格中，一個晶體不對稱單位包含了20個獨立的VP2 蛋白分子，VP2 蛋白結構主要可區分為三個區域，分別為具有Swiss-roll 拓撲結構的shell domain 和protrusion domain，以及由α螺旋結構所組成的base domain，三個VP2蛋白會形成一個三聚體結構，此三聚體為次病毒顆粒組成的基本架構，另外，於結構中發現有一鈣離子存在於VP2三聚體中，一個鈣離子藉由和三個VP2 蛋白分子的Asp31 和Asp174結合來穩定VP2三聚體。為了了解此鈣離子的功能，利用EGTA除去二價鈣離子後以凝膠電泳和電子顯微鏡分析此次病毒顆粒的形態，結果顯示鈣離子不僅只是維持其四級結構的穩定，且可調控此病毒顆粒的膨脹和離解，最後提出了一個以鈣離子為主的病毒組裝機制: 三個VP2 蛋白藉由與鈣離子的結合而形成穩定的VP2三聚體，20個VP2三聚體再進一步組裝成更大的病毒顆粒。而於一個晶體不對稱單位所得到的20 個獨立的VP2 蛋白單體結構則顯示了20種不同的構型，經過比較後，發現位於病毒表面的四段迴圈具有最大的構形差異，且這塊區域為中和性抗體的主要結合區，因此藉由分析這些抗體結合區的結構可以了解抗體和抗原的交互作用。對傳染性華氏囊病毒次病毒顆粒結構的了解將有助於新疫苗的發展。
中文摘要:
病毒的蛋白酶 (proteases) 可以當做目標蛋白來進行抗病毒療法之研究，X-ray晶體結構可協助其抑制劑的設計。有些金屬離子 (Cu2+, Hg2+, Zn2+) 和 金屬共軛分子可抑制 cysteine 蛋白酶的活性，為了了解這類金屬抑制劑的抑制模式並合成更好的抑制劑。本論文利用蛋白質晶體學來分析Coronaviridae和Piconaviridae的蛋白酶，3C-like (3CL) 和3C 蛋白酶，及其與金屬共軛抑制劑所形成的複合物，藉以了解這一類抑制劑的抑制機制。針對severe acute respiratory syndrome (SARS) -associated coronavirus (CoV)，五種金屬共軛抑制劑 (PMA 、TDT 、EPDTC 、JMF1586 和JMF1600) 可有效抑制其3C-like 蛋白酶的活性並結合形成複合體，由得到的複合體結構可得知二種主要的抑制模式: 其一，PMA 的汞離子在S3 受質結合區與氨基酸C44 、M49 和Y54 以方形平面幾何形成配位鍵結，其二，另外四種鋅共軛抑制劑的鋅離子則與活性區的Histidine和Cysteine以四面體幾何形成配位鍵結。另外，Human coronavirus 229E (HCoV-229E) 的3CL蛋白酶和Coxsackie B type 3 (CVB3) 的3C 蛋白酶具有和SARS-CoV 的3CL蛋白酶一樣的催化殘基。在此，我們解出第一個CVB3 3C蛋白酶晶體結構，並得到CVB3 3C和HCoV-229E蛋白酶分別與鋅共軛抑制劑EPDTC形成複合體的晶體結構。EPDTC對這兩個蛋白酶的抑制模式如同抑制SARS-CoV 3CL 蛋白酶一般，EPDTC以鋅離子與這兩個蛋白酶的催化殘基Histidine 及 Cysteine形成配位鍵結。針對抗病毒藥物的設計，這個以鋅離子為中心的四面體配位鍵結模式可以當做設計更好病毒抑制劑的開端。

Crystal Structure of Infectious Bursal Disease Virus VP2 Subviral Particle at 2.6 Å Resolution: Implications in Virion Assembly and Immunogenicity
Abstract
Infectious bursal disease virus (IBDV) is responsible for the hightly contagious and immunosuppressive disease in young chicken. The structural protein VP2 of IBDV spontaneously forms a dodecahedral T=1 subviral particle (SVP), and is a primary immunogen of the virus, understand of its structure is efficient for vaccine development. In this study, the structure of IBDV SVP was determined in a cubic crystal and refined to 2.6Å resolution. It contains 20 independent VP2 subunits in a crystallographic asymmetric unit. Each subunit is folded mainly into a shell domain and a protrusion domain, both with the Swiss-roll topology, plus a small helical base domain. Three VP2 subunits constitute a tight trimer, which is the building block of IBDV (sub)viral particles. The structure revealed a calcium ion bound to three pairs of symmetry-related Asp31 and Asp174 to stabilize the VP2 trimer. To investigate the effect of Ca2+ on the IBDV SVP structure, we used EGTA to remove the divalent ion and analyzed the particle morphology by gel electrophoresis and electron microscopy, and the results indicated that the metal-ion may be important not only in maintaining highly stable quaternary structure but also in regulating the swelling and dissociation of the icosahedral particles. A Ca2+-dependent assembly pathway was thus proposed, which involves further interactions between the trimers. The 20 independent subunits showed conformational variations, with the surface loops of the protrusion domain being the most diverse. These loops are targets of the neutralizing antibodies. Several common interactions between the surface loops were clearly observed, suggesting a possible major conformation of the immunogenic epitopes. Knowledge of the three-dimensional structure of SVP may be useful in rationally incorporating important foreign epitopes into the loop region to create engineered recombinant SVP as new potent immunogens or vaccines.

Structural Basis of Metal-conjugated Complexes as 3C and 3C-like Protease Inhibitors
Abstract
Viral proteases have been pursued for anti-virus therapy, and their crystal structures were used to assist the design of inhibitors. Some metals (Cu2+, Hg2+, Zn2+) and metal-conjugated compounds showed cysteine protease inhibition activity. Here, to elucidate the metal-inhibitor binding mode and to synthesize better inhibitors, 3C-like protease from Coronaviridae and 3C protease from Piconaviridae complexed with metal-conjugated inhibitors were analyzed crystallographically.
Five active metal-conjugated inhibitors (PMA, TDT, EPDTC, JMF1586 and JMF1600) bound with the 3C-like protease (3CLpro) of severe acute respiratory syndrome (SARS)-associated coronavirus (CoV) were determined. The complex structures reveal two major inhibition modes: Hg2+-PMA is coordinated to C44, M49 and Y54 with a square planar geometry in the S3 pocket, whereas each Zn2+ of the four zinc-inhibitors is tetrahedrally coordinated to the His-Cys catalytic dyad. 3CLpro of human coronavirus 229E (HCoV-229E) and 3C proteases of Coxsackie B viruses type 3 (CVB3) also have the His-Cys catalytic residues as 3CLpro of SARS-CoV. The first crystal structures of CVB3 3Cpro, and the crystal structure of 3Cpro from CVB3 and 3CLpro from HCoV-229E in complex with the inhibitor EPDTC were also determined. The zinc ion of EPDTC is again tetrahedrally coordinated to the His-Cys catalytic residues of CVB3 3Cpro and HCoV-229E 3CLpro. For anti-virus drug design, this Zn2+-centered coordination pattern would serve as a starting platform for inhibitor optimization.

Table of Contents
List of Figures (1).…………………………………………………..…………..……..…….....…....I List of Tables (1)……………………………………………………....……..…..……...….....…....II List of Figures (2).……………………………….…..……………..……..……..……..…….…....III List of Tables (2)………….……………………………………...…....……..…………..……......IV Prefatorial Remark……………………………………………….…………………………………V Abstract (1) ………….………………………………………....……..……..….………………... VI中文摘要(一)…………………………………………………………….…………….….…..….VII Abstract (2)………………………………………..………………..….……..……..…..…….…VIII中文摘要(二)……………………………………………………………………….…...….……..IX Abbreviations…………………….……………………………..………..…..……...……….....…..X

Part (1) Crystal structure of infectious bursal disease virus VP2 subviral particle at 2.6 Å resolution: Implications in virion assembly and immunogenicity
Chapter 1.1. Introduction………………………….…………………………….….………….…..2 1.1.1. Background and genome structure of IBDV……………………………...…….…….……….2 1.1.2. Immunogenicity of IBDV……………………………………………………....…….………..2 1.1.3. Structure of IBDV and Virion assembly……………………………..……….……….………3 1.1.4. Crystallography in SVP……………………………………………………...…….…………..4 Chapter 1.2. Material and Methods……………………………………………...………………...5 1.2.1. Expression and Purification…………………………………………...……………………….5 1.2.2. Crystallization and data collection………………………………..………….………..………5 1.2.3. Computer programs…………………………………………………...……………………….6 1.2.4. Molecular replacement……………..………………….……………………………………....7 1.2.5. Model building………………..……………………………………………………………….8 1.2.6. Heavy atom sites………………………………………………………………………...……..8 1.2.7. Sequence comparison……………………..……………………………………….…………..9 1.2.8. Determination of metal content by ICP-MS…………………………………………………...9 1.2.9. Gel electrophoresis……………………..………………………………………….…………..9 1.2.10. Electron microscopy………………………………...…………………………….…..…….10 Chapter 1.3. Results…………………….………………………………………………………….11 1.3.1. Monomer VP2 structure……………………..…………………………………………….....11 1.3.2. Trimer structure…………………………………………….…………………………...……12 1.3.3. Roles of calcium ion……………….…………………………………………………....……14 Chapter 1.4. Discussion………………………………...…………………………………….…....16 1.4.1. Particle assembly .…..…………….……………………..…………………………….……..16 1.4.2. Surface charge………………………………………………………………………….…….17 1.4.3. Functional loops……………………………………………………………….…..…………17 Figures (1)………………………………………………………….……………………………….20 Tables (1)……………………………………………….…………………………………………...42

Part (2) Structural basis of metal-conjugated complexes as 3C and 3C-like protease inhibitors
Chapter 2.1. Introduction……………………….…………….…………………………………..47 2.1.1. SARS-CoV, HCoV-229E and CVB……………………………………………….………….47 2.1.2. 3C and 3C-like protease…………………………………..…….………………….………...48 2.1.3. Protease inhibitors………………………………………………………………….…...……48 Chapter 2.2. Material and Methods…………………………………………………….………...50 2.2.1. Inhibitors and inhibition assay…………………………………………………….………….50 2.2.2. Preparation of SARS-CoV 3CLpro, CoV-229E 3CLpro and CVB3 3Cpro…………….…….…50 2.2.3. Crystallography of SARS-CoV 3CLpro complexd with metal-conjugated inhibitors……...…51 2.2.4. Crystallography of CVB3 3Cpro, HCoV 229E 3CLpro, and in complex with EPDTC….…….52 Chapter 2.3. Results……………………..……………………………………………………....…54 2.3.1. Overall structures of SARS 3CLpro…………………………………………………...............54 2.3.2. Binding mode of PMA, TDT and EPDTC………………………………………….………..54 2.3.3. Binding modes of JMF1586 and JMF1600 and inhibition activity…………….…….………56 2.3.4. Structures of HCoV 229E 3CLpro in complex with EPDTC…………………….……………56 2.3.5. Structures of CVB3 3Cpro…………………………………………………………..……..….57 2.3.6. Structures of CVB3 3Cpro in complex with EPDTC………………………………………….58 Chapter 2.4. Discussion…………………………..…………………………………………….….60 2.4.1. Comparison of 3CLpro and 3Cpro………..……………………………….……………………60 2.4.2. PMA inhibit SARS-CoV 3CLpro…………………………………………….………………..60 2.4.3. EPDTC inhibit SARS-CoV 3CLpro, HCoV 229E 3CLpro and CVB3 3Cpro…….…………….61 Figures (2)………………………………………………………………………………….…….…63 Tables (2)………………………………………………………………………………….…….…..75 References……………………………………………………………………………………….….78Publications…………………………………………...…………………………………..…..……88

List of Figures (1)
Figure 1. Transmission electron microscopy (TEM) picture of SVP and IBDV virion. ……..…20 Figure 2. SVP crystals and derivative crystals. …………………………………………….…….21 Figure 3. Self-rotation function maps of an SVP crystal. ……………………………….……..…22 Figure 4. Symmetry of SVP and H253 geometry. ………………………………………………..23 Figure 5. Packing of SVP in the crystal. .……………….………………………………………...24 Figure 6. Cross rotation function of SVP. …………….…………………………………………..25 Figure 7. Representive electron density maps. ……………………………………………...……26 Figure 8. Heavy atom sites. ………………………………………………………..……..………27 Figure 9. Subunit structure of VP2. ……………………………………………………….......….28 Figure 10. Topology of VP2. …………………..………………………….…………..…...……..29 Figure 11. Stereo view of superimposed VP2 models. ………………………………..………….30 Figure 12. Topology diagram. ……………………………………………………………………31 Figure 13. Temperature factor distribution. …………………………….…….…………...…….32 Figure 14. Overall structure of the IBDV subviral particle (SVP). ….………………………..….33 Figure 15. The electrostatic surface potential for a VP2 pentamer. …………………………...…34 Figure 16. Sequence alignment. …………………………………………………………….…....35 Figure 17. Trimer structure of VP2. …………………………………………………………..….36 Figure 18. Cavity and ions in VP2 trimer. ………………………………………………………..37 Figure 19. Ions binding sites. ………………………………………………………………….....38 Figure 20. Effects of EGTA on SVP. ……………………………………………………...……...39 Figure 21. Proposed assembly of IBDV SVP. ……………………………….…………..……….40 Figure 22. Loop structures of IBDV VP2. ………………………………………………………..41

I

List of Tables (1)
Table 1. Data collection and refinement statistics of the IBDV crystals. …………………..…….42 Table 2. Progress of refinement of the IBDV crystal structure. ………………………..……..….43 Table 3. Metal content in SVP solution. ……………………………………………………….....44 Table 4. Summary of subunit properties. ………………………………………………….…...…45



















II
List of Figures (2)
Figure 1. Chemical structures and inhibition parameters of inhibitors. ……………..….……....…63 Figure 2. Crystal structures of inhibited 3CLpro. ………………………………..…….….….….…64 Figure 3. The active site of 3CLpro with the bound PMA. …………….……...…………..……….65 Figure 4. Zinc-conjugated compounds bound to SARS-CoV 3CLpro. ………..………….…..……66 Figure 5. Schematic representation of zinc-centered geometry. ………………....………..………67 Figure 6. The 2Fo-Fc electron density maps superimposed on the structures. …….……….….…..68 Figure 7. A model of the SARS 3CLpro complexed with intact EPDTC. ………….……...….....…69 Figure 8. Crystal structures of inhibited HCoV-229E 3CLpro. ………………….…….….…….….70 Figure 9. Crystal structures of CVB3 3Cpro. …………………………………………..…….…….71 Figure 10. CVB3 3Cpro superimposed with SARS 3CLpro. ………………….………...….….…....72 Figure 11. EPDTC bound to three different 3C(L)pro. ………………………….…….…...…....…73 Figure 12. Design the Zn-conjugated compounds. ……………………………………...…..…….74











III

List of Tables (2)
Table 1. Data collection and refinement statistics of SARS 3CLpro complexes. ………..…..…....75 Table 2. Data collection and refinement statistics of 229E 3CLpro complex. …………….………76 Table 3. Data collection and refinement statistics of CV 3Cpro and complex. ……………..……..77



















IV

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