本文選題：可溶性鳥苷酸環(huán)化酶　切入點(diǎn)：血紅素輔基　出處：《吉林大學(xué)》2010年博士論文　論文類型：學(xué)位論文

【摘要】： 可溶性鳥苷酸環(huán)化酶(soluble Guanylate Cyclase, sGC)作為NO-cGMP信號(hào)轉(zhuǎn)導(dǎo)通路中重要的樞紐蛋白,與體內(nèi)諸多生理、病理現(xiàn)象如神經(jīng)信號(hào)傳導(dǎo)、血管舒張、抗血小板凝集、抗平滑肌增生、中風(fēng)、糖尿病和癌癥等息息相關(guān)。氣體配基分子一氧化氮(Nitric Oxide,NO)是sGC體內(nèi)的主要激活因子,開啟該酶的活性使GTP轉(zhuǎn)化為第二信使cGMP。 在缺乏sGC晶體結(jié)構(gòu)的情況下,首先,我們通過多序列同源比對(duì)方法構(gòu)建了sGC血紅素結(jié)合結(jié)構(gòu)域的同源模型,并以分子動(dòng)力學(xué)對(duì)模型進(jìn)行了優(yōu)化和平衡。然后,我們通過LES分子動(dòng)力學(xué)模擬,比對(duì)了sGC血紅素結(jié)合結(jié)構(gòu)域與原核類似蛋白的氣體遷移之關(guān)系,從原子層面解釋和討論sGC對(duì)氧氣的區(qū)分機(jī)制。最后,我們運(yùn)用密度泛函理論,進(jìn)行了不同配基RNO分子與血紅素輔基結(jié)合的模型研究,借助配位化學(xué)和分子軌道理論,解釋具有sGC激活性質(zhì)的RNO類化合物激活sGC的機(jī)理和規(guī)律,為sGC激活劑的虛擬篩選和sGC激活機(jī)制的研究奠定了理論基礎(chǔ)。
[Abstract]:Soluble guanylate cyclase Guanylate cyclase (sGCase), as an important pivotal protein in NO-cGMP signal transduction pathway, is associated with many physiological and pathological phenomena such as nerve signal transduction, vasodilation, anti-platelet agglutination, anti-smooth muscle hyperplasia, apoplexy. The gas ligand nitric oxide (no) is the main activator of sGC, which turns on the activity of the enzyme to transform GTP into second messenger cGMP. In the absence of sGC crystal structure, we first constructed the homology model of sGC heme binding domain by multiple sequence homology alignment method, and optimized and balanced the model by molecular dynamics. By means of LES molecular dynamics simulation, we compared the relationship between sGC heme binding domain and the gas transport of prokaryotic similar proteins, and explained and discussed the oxygen differentiation mechanism of sGC at the atomic level. Finally, we used density functional theory (DFT). The binding models of different ligand RNO molecules to heme cogroups were studied. By means of coordination chemistry and molecular orbital theory, the mechanism and regularity of sGC activation by RNO compounds with sGC activation properties were explained. It lays a theoretical foundation for the virtual screening of sGC activators and the study of sGC activation mechanism.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R341

【引證文獻(xiàn)】

相關(guān)博士學(xué)位論文 前1條

1 余淑嫻;金屬鎳、錫絡(luò)合物催化烯烴活化及聚合反應(yīng)機(jī)理研究[D];南昌大學(xué);2014年

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本文編號(hào)：1603456