近日,來自美國杜克大學的研究人員確定了一種小分子物質的結構,這種小分子物質可以協助化療並且可以協助抗病毒藥物進入細胞,研究者的研究將幫助我們創造出更多的副作用少、效用更高的藥物。研究者Seok-Yong Lee表示,「知道這種轉運分子的結構和性質將成為改變一些傳統化學療法的關鍵一步,比如說,我們可以讓這種分子在體內抑制腫瘤細胞的生長。研究者的相關研究成果已於3月11日刊登在了國際著名雜誌Nature上。
這種轉運分子命名為集中性的核苷轉運分子(Concentrative Nucleoside Transporter,CNT),通過移動構成DNA和RNA的基本結構單元-核苷酸來工作,CNT將單核苷酸從細胞外轉移到細胞內,不僅如此,CNT也可以轉運類似核苷酸的藥物通過細胞膜,一旦藥物進入細胞,就會被修飾成核苷酸類,然後隨著DNA的組件過程被摻入進DNA,從而通過分離腫瘤細胞的DNA來阻止其複製。
研究者表示,目前他們已經發現了這種轉運分子(CNT)的基本結構,而且這種轉運分子可以以特殊的方式來識別核苷類藥物,並且將其運輸到特定的組織,而轉運分子有三種形式,可以是被不同種的藥物並且運輸至不同的組織。如果可以增強轉運分子和藥物之間的反應結合度,那麼將不必給腫瘤細胞中轉運入過多的無效藥物,從而對人體引起副作用,而且如果知道這種轉運分子的形狀,將會更有助於科學家設計出和轉運分子結合性更好的藥物。
研究者Lee表示,「當藥物在轉運分子的協助下進入腫瘤細胞的同時,也會進入正常的細胞,所以針對腫瘤細胞的低劑量藥物非常有必要,因為劑量過高,對正常細胞的副作用會非常明顯,我們的目的是在保護病人的情況下殺死腫瘤細胞。」
研究者研究了霍亂弧菌的轉運分子,這種細菌的轉運分子可以為我們研究人類的轉運分子提供一個很好的模型,因為它們擁有類似的胺基酸序列,通過研究發現,細菌和人類的轉運分子都依靠鈉梯度來講核苷類藥物或者分子運輸進入細胞。下一步,研究者將試圖去理解轉運分子識別特定化學藥物時候的一些特徵,並且最終設計出一些容易被轉運而且容易進入靶細胞的藥物。(生物谷:T.Shen編譯)
Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4 Å
Zachary Lee Johnson, Cheom-Gil Cheong & Seok-Yong Lee
Nucleosides are required for DNA and RNA synthesis, and the nucleoside adenosine has a function in a variety of signalling processes1, 2. Transport of nucleosides across cell membranes provides the major source of nucleosides in many cell types and is also responsible for the termination of adenosine signalling. As a result of their hydrophilic nature, nucleosides require a specialized class of integral membrane proteins, known as nucleoside transporters (NTs), for specific transport across cell membranes. In addition to nucleosides, NTs are important determinants for the transport of nucleoside-derived drugs across cell membranes3, 4, 5. A wide range of nucleoside-derived drugs, including anticancer drugs (such as Ara-C and gemcitabine) and antiviral drugs (such as zidovudine and ribavirin), have been shown to depend, at least in part, on NTs for transport across cell membranes4, 6, 7, 8, 9, 10, 11, 12, 13. Concentrative nucleoside transporters, members of the solute carrier transporter superfamily SLC28, use an ion gradient in the active transport of both nucleosides and nucleoside-derived drugs against their chemical gradients. The structural basis for selective ion-coupled nucleoside transport by concentrative nucleoside transporters is unknown. Here we present the crystal structure of a concentrative nucleoside transporter from Vibrio cholerae in complex with uridine at 2.4 Å. Our functional data show that, like its human orthologues, the transporter uses a sodium-ion gradient for nucleoside transport. The structure reveals the overall architecture of this class of transporter, unravels the molecular determinants for nucleoside and sodium binding, and provides a framework for understanding the mechanism of nucleoside and nucleoside drug transport across cell membranes.