美国科学家近日首次确定了一种名为P-醣蛋白(P-gp)的蛋白结构,该蛋白会将许多化疗药物阻挡在细胞之外,这是癌细胞对化疗药物具有抗性的主要原因之一。弄清这一蛋白的结构将有助于科学家设计更有效的抗癌药物。相关论文发表在3月27日的《科学》(Science)杂志上。
P-gp于1976年被首次发现,它位于肠道、肾脏、脑等处细胞的细胞膜上,功能是作为“看门人”,赶走潜在的有害物质。不过问题在于,它不仅运出对细胞有害的物质,同时也会驱赶针对癌细胞、感染HIV的细胞的药物。
在此次研究中,美国斯克里普斯研究所联合美国德州理工大学,运用X-射线结晶学成功地确定了P-gp的结构。
论文通讯作者、斯克里普斯研究所研究人员Geoffrey Chang说:“确定这一蛋白的结构是一个重要的进展,我们希望它只是个开始,后续还会有更多的突破。这一结构是一个精良的工具,可帮助我们理解P-gp如何将药物运出细胞,并帮助设计能规避P-gp阻药抗性的新药物。这真让人兴奋!”
美国普通医学科学研究所(NIGMS)研究人员Jean Chin说:“我们早已知道,P-gp对于癌症患者多药抗性的产生起关键作用,此次研究帮助我们理解了这一蛋白如何能够作用于种类如此宽泛的化合物。将来,科学家也许能够利用这些结晶结构设计化学制剂,阻断P-gp的活性并恢复对于化疗药物的敏感性。”(生物谷Bioon.com)
生物谷推荐原始出处:
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.