美國(guó)科學(xué)家近日首次確定了一種名為P-醣蛋白（P-gp）的蛋白結(jié)構(gòu),，該蛋白會(huì)將許多化療藥物阻擋在細(xì)胞之外,，這是癌細(xì)胞對(duì)化療藥物具有抗性的主要原因之一,。弄清這一蛋白的結(jié)構(gòu)將有助于科學(xué)家設(shè)計(jì)更有效的抗癌藥物,。相關(guān)論文發(fā)表在3月27日的《科學(xué)》（Science）雜志上,。
P-gp于1976年被首次發(fā)現(xiàn),，它位于腸道、腎臟,、腦等處細(xì)胞的細(xì)胞膜上,，功能是作為“看門人”，趕走潛在的有害物質(zhì),。不過(guò)問(wèn)題在于,，它不僅運(yùn)出對(duì)細(xì)胞有害的物質(zhì)，同時(shí)也會(huì)驅(qū)趕針對(duì)癌細(xì)胞,、感染HIV的細(xì)胞的藥物,。
在此次研究中，美國(guó)斯克里普斯研究所聯(lián)合美國(guó)德州理工大學(xué),，運(yùn)用X-射線結(jié)晶學(xué)成功地確定了P-gp的結(jié)構(gòu),。
論文通訊作者、斯克里普斯研究所研究人員Geoffrey Chang說(shuō)：“確定這一蛋白的結(jié)構(gòu)是一個(gè)重要的進(jìn)展,，我們希望它只是個(gè)開(kāi)始,，后續(xù)還會(huì)有更多的突破。這一結(jié)構(gòu)是一個(gè)精良的工具,，可幫助我們理解P-gp如何將藥物運(yùn)出細(xì)胞,，并幫助設(shè)計(jì)能規(guī)避P-gp阻藥抗性的新藥物。這真讓人興奮,！”
美國(guó)普通醫(yī)學(xué)科學(xué)研究所（NIGMS）研究人員Jean Chin說(shuō)：“我們?cè)缫阎?，P-gp對(duì)于癌癥患者多藥抗性的產(chǎn)生起關(guān)鍵作用，此次研究幫助我們理解了這一蛋白如何能夠作用于種類如此寬泛的化合物,。將來(lái),，科學(xué)家也許能夠利用這些結(jié)晶結(jié)構(gòu)設(shè)計(jì)化學(xué)制劑，阻斷P-gp的活性并恢復(fù)對(duì)于化療藥物的敏感性,。”（生物谷Bioon.com）
生物谷推薦原始出處：
Science 27 March 2009:DOI: 10.1126/science.1168750
Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding
Stephen G. Aller,1 Jodie Yu,1 Andrew Ward,2 Yue Weng,1,4 Srinivas Chittaboina,1 Rupeng Zhuo,3 Patina M. Harrell,3 Yenphuong T. Trinh,3 Qinghai Zhang,1 Ina L. Urbatsch,3 Geoffrey Chang1
P-glycoprotein (P-gp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance (MDR) in the treatment of cancers. Substrate promiscuity is a hallmark of P-gp activity, thus a structural description of poly-specific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo P-gp at 3.8 angstroms reveals an internal cavity of 6000 angstroms cubed with a 30 angstrom separation of the two nucleotide-binding domains. Two additional P-gp structures with cyclic peptide inhibitors demonstrate distinct drug-binding sites in the internal cavity capable of stereoselectivity that is based on hydrophobic and aromatic interactions. Apo and drug-bound P-gp structures have portals open to the cytoplasm and the inner leaflet of the lipid bilayer for drug entry. The inward-facing conformation represents an initial stage of the transport cycle that is competent for drug binding.
1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
2 Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
3 Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
4 College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072 P. R. China.
