美國科學家近日首次確定了一種名為P-醣蛋白（P-gp）的蛋白結構，該蛋白會將許多化療藥物阻擋在細胞之外,，這是癌細胞對化療藥物具有抗性的主要原因之一,。弄清這一蛋白的結構將有助于科學家設計更有效的抗癌藥物。相關論文發(fā)表在3月27日的《科學》（Science）雜志上,。
P-gp于1976年被首次發(fā)現,，它位于腸道、腎臟,、腦等處細胞的細胞膜上,，功能是作為“看門人”，趕走潛在的有害物質,。不過問題在于,，它不僅運出對細胞有害的物質，同時也會驅趕針對癌細胞,、感染HIV的細胞的藥物,。
在此次研究中，美國斯克里普斯研究所聯合美國德州理工大學,，運用X-射線結晶學成功地確定了P-gp的結構,。
論文通訊作者、斯克里普斯研究所研究人員Geoffrey Chang說：“確定這一蛋白的結構是一個重要的進展,，我們希望它只是個開始,，后續(xù)還會有更多的突破。這一結構是一個精良的工具,，可幫助我們理解P-gp如何將藥物運出細胞,，并幫助設計能規(guī)避P-gp阻藥抗性的新藥物。這真讓人興奮,！”
美國普通醫(yī)學科學研究所（NIGMS）研究人員Jean Chin說：“我們早已知道,，P-gp對于癌癥患者多藥抗性的產生起關鍵作用，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,，科學家也許能夠利用這些結晶結構設計化學制劑,，阻斷P-gp的活性并恢復對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.
