日科學(xué)家證明轉(zhuǎn)運(yùn)蛋白把藥物排出細(xì)胞的機(jī)制

2013年4月8日 | Filed under: 藥物化學(xué),文獻(xiàn)綜合 | Posted by: 編輯 D

?作者：藍(lán)建中

日本一個(gè)研究小組日前在《自然》雜志網(wǎng)絡(luò)版上報(bào)告說(shuō)，他們弄清了細(xì)菌細(xì)胞膜上的轉(zhuǎn)運(yùn)蛋白的立體結(jié)構(gòu)，轉(zhuǎn)運(yùn)蛋白能將藥物排出細(xì)胞從而讓細(xì)菌產(chǎn)生抗藥性。這一發(fā)現(xiàn)有望幫助研發(fā)抗菌新藥。

東京大學(xué)的研究小組以耐受高溫環(huán)境的嗜熱古菌的轉(zhuǎn)運(yùn)蛋白為模型，使其在脂質(zhì)中結(jié)晶，然后利用Ｘ射線詳細(xì)分析了其立體結(jié)構(gòu)。最終確認(rèn)了其負(fù)責(zé)直接排出抗生物質(zhì)的部分。研究人員將氨基酸連接成環(huán)狀形成肽，成功阻止了嗜熱古菌轉(zhuǎn)運(yùn)蛋白功能，使其無(wú)法排出抗生物質(zhì)。

多重耐藥菌是指有多重耐藥性的病原菌，多種抗生物質(zhì)對(duì)其都無(wú)法發(fā)揮作用。研究小組認(rèn)為，如果能夠研發(fā)出阻礙多重耐藥菌轉(zhuǎn)運(yùn)蛋白功能的物質(zhì)，就有望開(kāi)發(fā)強(qiáng)有力的抗菌新藥。

【原文摘要】

Structural basis for the drug extrusion mechanism by a MATE multidrug transporter

Multidrug and toxic compound extrusion (MATE) family transporters are conserved in the three primary domains of life (Archaea, Bacteria and Eukarya), and export xenobiotics using an electrochemical gradient of H+ or Na+ across the membrane. MATE transporters confer multidrug resistance to bacterial pathogens and cancer cells, thus causing critical reductions in the therapeutic efficacies of antibiotics and anti-cancer drugs, respectively. Therefore, the development of MATE inhibitors has long been awaited in the field of clinical medicine. Here we present the crystal structures of the H+-driven MATE transporter from Pyrococcus furiosus in two distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 2.1–3.0?? resolutions. The structures, combined with functional analyses, show that the protonation of Asp?41 on the amino (N)-terminal lobe induces the bending of TM1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities. The strongest inhibitory peptide that occupies the N-lobe cavity may pave the way towards the development of efficient inhibitors against MATE transporters.

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