真核生物神經(jīng)遞質(zhì)（eukaryotic neurotransmitter）鈉轉(zhuǎn)運(yùn)體（NSSs）是一種能終止神經(jīng)傳遞過程的物質(zhì),，其作用機(jī)理主要是通過鈉驅(qū)動(dòng)的再吸收,，因此鈉轉(zhuǎn)運(yùn)體是多種抗抑郁劑以及中樞神經(jīng)興奮劑作用的目標(biāo),。而在原核生物中,，存在一種類似功能的NSS物質(zhì)—LeuT,，LeuT是依賴于鈉離子的神經(jīng)轉(zhuǎn)運(yùn)蛋白在細(xì)菌等中的一種同源結(jié)構(gòu),，其晶體結(jié)構(gòu)表現(xiàn)出一種一個(gè)亮氨酸及兩個(gè)鈉離子結(jié)合在一起的閉合狀態(tài),，但是該物質(zhì)的晶體結(jié)構(gòu)卻無法全面揭示轉(zhuǎn)運(yùn)的分子學(xué)機(jī)制,。
在2008年6月20日出版的《分子細(xì)胞》（Molecular Cell）上,，來自美國的一組科學(xué)家發(fā)表文章稱，他們找到了依賴于鈉離子的底物轉(zhuǎn)運(yùn)循環(huán),。通過一種稱為“拉伸分子動(dòng)力學(xué)模擬”（steered molecular dynamics simulation）的技術(shù),，研究小組找到了LeuT的底物轉(zhuǎn)運(yùn)途徑,。在計(jì)算模擬過程中，科研人員發(fā)現(xiàn)存在一個(gè)次級(jí)底物結(jié)合位點(diǎn),，該位點(diǎn)位于胞外前庭（extracellular vestibule）,，并且其包含的殘留物顯示最近發(fā)生過與三環(huán)抗抑郁劑（tricyclic antidepressants）的結(jié)合。
進(jìn)一步實(shí)驗(yàn)顯示,，兩個(gè)結(jié)合位點(diǎn)能同時(shí)被占據(jù),，次級(jí)位點(diǎn)的底物可變構(gòu)觸發(fā)細(xì)胞內(nèi)鈉離子以及初級(jí)位點(diǎn)底物的釋放，因此其作用相當(dāng)于“協(xié)同轉(zhuǎn)運(yùn)效應(yīng)子”,。由于三環(huán)抗抑郁劑能結(jié)合于該次級(jí)位點(diǎn),，初級(jí)位點(diǎn)的底物釋放不會(huì)被促進(jìn)，也就是說,，抗抑郁類藥物和中樞神經(jīng)興奮劑等能和結(jié)合底物產(chǎn)生競爭,，而與底物不同的是，當(dāng)這些抗抑郁劑和興奮劑結(jié)合到位點(diǎn)上之后,，并不能像底物一樣觸發(fā)釋放,，因此抗抑郁劑可作為協(xié)同轉(zhuǎn)運(yùn)解偶聯(lián)劑，并起到抑制轉(zhuǎn)運(yùn)的作用,。（生物谷Bioon.com）
生物谷推薦原始出處：
Molecular Cell,，Vol 30, 667-677, 20 June 2008，Lei Shi, Jonathan A. Javitch
The Mechanism of a Neurotransmitter:Sodium Symporter—Inward Release of Na+ and Substrate Is Triggered by Substrate in a Second Binding Site
Lei Shi,1,2,7 Matthias Quick,3,6,7 Yongfang Zhao,3 Harel Weinstein,1,2 and Jonathan A. Javitch3,4,5,6,
1 Department of Physiology and Biophysics, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA
2 HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA
3 Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA
4 Department of Psychiatry, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA
5 Department of Pharmacology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA
6 Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA
Summary
Eukaryotic neurotransmitter:sodium symporters (NSSs), targets for antidepressants and psychostimulants, terminate neurotransmission by sodium-driven reuptake. The crystal structure of LeuTAa, a prokaryotic NSS homolog, revealed an occluded state in which one leucine and two Na+ ions are bound, but provided limited clues to the molecular mechanism of transport. Using steered molecular dynamics simulations, we explored the substrate translocation pathway of LeuT. We identified a second substrate binding site located in the extracellular vestibule comprised of residues shown recently to participate in binding tricyclic antidepressants. Binding and flux experiments showed that the two binding sites can be occupied simultaneously. The substrate in the secondary site allosterically triggers intracellular release of Na+ and substrate from the primary site, thereby functioning as a “symport effector.” Because tricyclic antidepressants bind differently to this secondary site, they do not promote substrate release from the primary site and thus act as symport uncouplers and inhibit transport.
