多巴胺運(yùn)輸?shù)鞍?DAT)是一種膜蛋白，將神經(jīng)傳輸物質(zhì)多巴胺從突觸間隙中清除,，將其輸入到周圍細(xì)胞的細(xì)胞溶質(zhì)內(nèi),，從而終止神經(jīng)傳輸物質(zhì)的信號(hào)。
Eric Gouaux及同事報(bào)告了與三環(huán)抗抑郁藥物“去甲替林”結(jié)合在一起的果蠅DAT的X-射線結(jié)構(gòu),。
這是迄今確定的一種真核生物神經(jīng)傳輸物質(zhì)鈉“共輸送體”的第一個(gè)晶體結(jié)構(gòu),。
果蠅DAT的整體結(jié)構(gòu)與LeuT的結(jié)構(gòu)相似，但作者也發(fā)現(xiàn)了幾個(gè)差別,，這些差別在真核蛋白的運(yùn)輸機(jī)制及其被磷酸化的調(diào)控中可能起重要作用,。（生物谷Bioon.com）
生物谷推薦的英文摘要
Nature doi:10.1038/nature12533
X-ray structure of dopamine transporter elucidates antidepressant mechanism
Aravind Penmatsa，Kevin H. Wang& Eric Gouaux
Antidepressants targeting Na+/Cl-coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However,， identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors,， and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels,， has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1， 3,， 6 and 8,， blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT， there are multiple distinctions,， including a kink in transmembrane helix 12 halfway across the membrane bilayer， a latch-like carboxy-terminal helix that caps the cytoplasmic gate,， and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a,， 5 and 7. Taken together， the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids,， thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses.
