报告题目：Structural Basis of Ion Selectivity and Gating of Short-chain Acid Channels
报告人：Da-Neng Wang, Ph.D.
Professor, Skirball Institute and Department of Cell Biology
NYU School of Medicine
主持人：冯新华 教授
时 间：2011年11月17日（星期四）下午2点
地 点：医学院综合楼205报告厅
Abstract：
Membrane transport in cells is a fundamental biological process that is mediated by various channel and transporter proteins. A major type of such proteins is secondary active membrane transporters, which use a solute gradient to drive the translocation of other substrates. The largest secondary transporter protein family known is the major facilitator superfamily (MFS), with more than one hundred thousand members identified to date. These proteins transport ions, sugars, sugar-phosphates, drugs, neurotransmitters, nucleosides, amino acids, peptides, and other hydrophilic solutes. Members of this superfamily are ubiquitous in all three kingdoms of living organisms, and many have medical or pharmacological relevance. For example, the mammalian glucose transporter Glut4 from muscle and adipose cells is responsible for their glucose uptake, a process that is impaired in type II diabetes. Inherited mutations in a related transporter, Glut1 from erythrocyte and brain blood barrier, cause Glucose Transporter 1 Deficiency Syndrome, a disease whose symptoms include infantile seizures and developmental delay. Similarly, mutations in human glucose-6-phospahte transporter (G6PT) cause glycogen storage disease type 1b. In bacteria, MFS proteins function principally for nutrient uptake, but some act as drug efflux pumps that confer antibiotic resistance.
We attempt to understand the mechanism of the MFS proteins by determining the crystal structure of a member of the transporter family. We crystallized GlpT, the glycerol-3-phosphate (G3P) transporter from the E. coli inner membrane. In E. coli, G3P serves both as a carbon and energy source and as a precursor for phospholipid biosynthesis. GlpT is an organic phosphate/inorganic phosphate (Pi) antiporter that functions for G3P uptake and is driven by a Pi gradient. We have determined the structure of GlpT at 3.3 Å resolution by X-ray crystallography. This is the first MSF structure ever determined to high resolution. The transporter structure suggests that the substrate translocation is by a single-binding site, alternating-access mechanism via a rocker-switch type of movement of the N- and C-terminal domains of the protein.
Selected Papers:
1. Jiang, Q.X., Wang, D.N. and MacKinnon, R. (2004) Electron microscopy analysis of KvAP voltage sensor paddle in an open conformation. Nature. 430, 806-810.
2. Law, C.J., Yang, Q., Soudant, C., Maloney, P.C. and Wang, D.N. (2007) Kinetic evidence is consistent with the rocker-switch mechanism of membrane transport by GlpT. Biochemistry. 46, 12190-12197.
3. Zhou, Z., Zhen, J., Karpowich, N.K., Goetz, R.M., Law, C.J., Reith, M.E.A. and Wang, D.N. (2007) LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science. 317, 1390-1393.
4. Karpowich, N.K. and Wang, D.N. (2008) Symmetric transporters for asymmetric transport. Science. 321, 781-782.
5. Zhou, Z., Zhen, J., Karpowich, N.K., Law, C.J., Reith, M.E.A. and Wang, D.N. (2009) Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures. Nat. Struct. Mol. Biol, 16, 652-657
6. Waight, A.B., Love, J. and Wang, D.N. (2010) Structure and mechanism of a pentameric formate channel. Nat. Struct. Mol. Biol. 17, 31-37.
7. Karpowich N.K. and Wang, D.N. (2010) Biophysics: Transporter in the spotlight. Nature 465, 171-172.
8. Czyzewski, B.K. and Wang, D.N. (2011) Identification and characterization of a bacterial hydrosulfide ion channel. Nature. In revision.
