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研究生:賴幸硏
研究生(外文):LAI,XING-YAN
論文名稱:抗精神病化合物 Kurarinone 與多巴胺受體 D1 和 D2 結合後的構象動態變化所產生的雙重功能的電腦模擬探究
論文名稱(外文):Computational Exploration of the Dual Functions Resulting From the Conformational Dynamics of Antipsychotic Compound Kurarinone Upon Binding to Dopamine Receptors D1 and D2
指導教授:許豪仁
指導教授(外文):HSU,HAO-JEN
口試委員:劉哲文梁剛荐
口試委員(外文):LIOU,JE-WENLEONG,MAX-K
口試日期:2023-12-14
學位類別:碩士
校院名稱:慈濟大學
系所名稱:生物醫學暨工程學系碩士班
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2024
畢業學年度:112
語文別:英文
論文頁數:96
中文關鍵詞:G蛋白耦合多巴胺受體構象變化
外文關鍵詞:GPCRdopamine receptorsstructural change
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G蛋白耦合受體家族是細胞膜上最大的蛋白受體家族,在人類的基因組中有約800個的基因編碼的G蛋白耦合受體,這類受體在結構上有相似的結構,七個跨膜螺旋,跨膜螺旋由細胞外環和細胞內環連接,細胞內環有G蛋白結合位點。他們參與許多細胞訊息傳遞過程,透過結合激動劑,將訊息傳遞到G蛋白,再根據結合G蛋白類型不同,刺激不同下游訊息反應。多巴胺受體屬於G蛋白耦合家族中A家族的成員之一。多巴胺受體依據結合G蛋白類型不同被分為「D1R類受體」和「D2R類受體」,D1R類受體結合促進性G蛋白,D2R類受體結合抑制性G蛋白。他們與許多神經系統調控有關,例如記憶、運動控制、認知等等,當多巴胺受體相關的功能異常會導致許多精神疾病,例如:帕金森氏症,其主要特徵是多巴胺能神經元喪失,導致多巴胺水平下降,現行藥物是使用D2R的促進劑治療帕金森氏症;精神分裂症,是一種複雜的精神疾病,現在給於治療藥物主要是以D2R抑制以降低症狀表現等等。苦參酮(kurarinone)是從中草藥苦參(Sophora flavescens)根萃取物中分離得出,kurarinone具有抗神經發炎功效,以前在動物實驗或是細胞實驗發現kurarinone具有抗子宮頸癌、肺癌、前列腺癌的功用;而近期研究發現,kurarinone可以結合D1R、D2R、D4R,但僅指出可以與多巴胺受體結合,對於kurarinone如何結合多巴胺受體及產生的結構效應仍不清楚。而在本研究,我們使用電腦模擬方式,探討kurarinone結合D1R 和D2R,觀察kurarinone對於蛋白質結構的影響,另外,我們還結合了其他部份激動劑比較結構差異,發現結合完全激動劑可以使構象完全活化,而結合部份激動劑,結構的改變程度弱於完全激動劑的構象,給予抑制劑,結構沒有明顯變化。在水通道分析,只在結合G蛋白的系統發現有連續水通道形成,可能原因是因為hydrophobic core的打開以及tyrosine toggle與內部水分子互動,與分子開關呈現的結果一致。而訊息網絡分析,發現當訊息終點在D1R受體的穿膜6區域上,是出現在活化態的系統中,而訊息停留在這個區域,也是G蛋白會互動的區域,但結合抑制劑的系統訊息傳遞到細胞內環3;在D2R受體則時發現在活化態的系統訊息會傳遞到穿膜6和細胞內環3,而在非活化態的系統則是停在細胞內環2,這是D1R以及D2R受體在結構上差異,D2R受體有較長的細胞內環3;而部份激動劑都展現不同的調控路徑。本篇利用電腦模擬方式,比較了所有系統,確認kurarinone在D1R扮演抑制劑,在D2R扮演激動劑,與先前他人研究一致。本次研究提供了D1R和D2R原子級別的構象變化,為設計D1R及D2R靶向藥物設計領域提供受體結合不同功能配體後結構動態變化的新見解。
The G protein-coupled receptor (GPCR) family represents the largest protein receptor family on the cell membrane, containing around 800 genes encoded by the human genome. These receptors share a common structural feature: seven transmembrane helices connected by extracellular and intracellular loops, the intracellular loops containing a G-protein binding site. They play crucial roles in various cellular signaling processes, transmitting messages to G proteins upon binding to agonists and stimulating diverse downstream responses depending on the G protein subtypes.
Dopamine receptors, belonging to class A of the GPCR family, comprise D1-like and D2-like subtypes. While D1-like receptors couple with stimulatory G proteins, D2-like receptors interact with inhibitory G proteins. These receptors involve many neurological functions, such as memory, motor control, and cognition. The dysfunction of dopamine receptors is linked to several psychological disorders. For example, Parkinson's disease is characterized by the loss of dopaminergic neurons, resulting in reduced dopamine levels, and is commonly treated with D2R agonists. Schizophrenia, a complicated psychiatric disorder, is mainly treated with D2R antagonists to reduce its symptoms.
Kurarinone, extracted from the root of Sophora flavescens, demonstrates anti-neuroinflammatory properties. Previous research has shown its potential to target cervical, lung, and prostate cancer in animal and cell experiments. Recent research has demonstrated its binding affinity with D1R, D2R, and D4R, but the specific mechanism of its interactions with dopamine receptors and resulting structural effects are still unclear.
In this research, computer simulations were used to study the binding of kurarinone to D1R and D2R and to observe its effects on protein structures. Furthermore, we compared the structural changes induced by different agonists and found that full agonists induced full conformational activation, whereas partial agonists induced less structural changes compared to full agonists, and antagonists showed no apparent structural changes. Our analysis of water channels revealed the creation of a continuous water pathway only in systems that bind to G-proteins. This event can be attributed to the opening of the hydrophobic core and the interactions between the tyrosine toggle and internal water molecules, in agreement with the observed results of the molecular switches.
Additionally, our network analysis demonstrated that when the signal endpoint is located in the transmembrane (TM) 6 region of the D1R receptor, it appears in the active state system, where the G protein interacts. Alternatively, in the antagonist-bound system, the signal is transmitted to the intracellular loop (ICL) 3. The D2R receptor's active system transmits signals to TM6 and ICL3, whereas in the inactive system, signal transmission stops at ICL2. D1R and D2R have structural differences, with the latter having a longer ICL3, which explains the difference in signaling pathways. Partial agonists showed different regulatory pathways. Using computer simulations, all systems were compared to confirm that kurarinone acts as an antagonist in D1R and as an agonist in D2R, in agreement with previous findings. This study provides new insights into the conformational changes on an atomic level in D1R and D2R and provides new perspectives on the structural dynamics following receptor binding with ligands of different functionalities.

1. Introduction 1
1.1. G-protein coupled receptors (GPCRs) 1
1.2. Overall structure of D1R and D2R. 3
1.3. Functions of ligands bound to dopamine receptors 7
1.4. Molecular switches impact on receptor activation 10
1.5. Water molecules impact receptor activation 12
1.6. Research Motivation and Aims 14
2. Materials and methods 15
2.1. Protein preparation 15
2.2. Ligand preparation 15
2.4. Molecular Dynamics (MD) simulations 18
2.5. Analysis 20
2.5.1. Root Mean Square Deviation (RMSD) 20
2.5.2. Porcupine plot analysis 20
2.5.3. Protein-Ligand interaction maps 21
2.5.4. Water network analysis (C-graphs) 22
2.5.5. Signaling transduction pathway analysis 23
2.5.6. Additional Analyses 23
2.5.7. Scientific Visualization and Graphical Representation: 24
2.5.8. Computer Hardware 24
3. Result 25
3.1. Validation of ligands docking to DRs 25
3.2. Conformational changes of DRs during MD simulations 27
3.2.1. The D1R-KR system showed an inactive state. 27
3.2.2. The D2R-KR system showed activated state. 30
3.3. Molecular switches of DRs systems during MD simulations 32
3.3.1. CWxP motif showed more contact during receptor activation. 35
3.3.2. PIF motif showed more contact during receptor activation. 37
3.3.3. Loss of contact with the hydrophobic core during receptor activation. 40
3.3.4. Tyrosine toggle showed more contact during receptor activation. 43
3.3.5. Ionic lock showed more contact during receptor activation. 45
3.4. The movement of TM6 outwards varied after binding to different ligands. 51
3.5. Key Residues Regulate Signal Transmission in the DRs 53
3.6. Dynamic Hydrogen Bond and the Formation of Continuous Pathways after G-protein Binding. 59
4. Discussion 64
4.1. Activation Mechanism of Dopamine Receptors 64
4.2. Structural Changes and Microswitch Dynamics 64
4.3. Ligand Interactions and Binding Site Dynamics 65
4.4. Signaling Pathway Analysis 69
4.5. Limitations and Future Directions 69
5. Conclusions 71
6. References 73

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