Molecular Determinants for Substrate Selectivity of OATP1B1 and 1B3

报告题目：Molecular Determinants for Substrate Selectivity of OATP1B1 and 1B3

报 告 人：贵春山博士

报告时间：2011年9月14日(周三)15:00

报告地点：独墅湖校区二期云轩楼1319

报告摘要：

Human organic anion transporting polypeptides (OATP) 1B1 and 1B3 are liver-specific transporters located at the basolateral membrane of hepatocytes and mediate uptake of amphipathic organic compounds from blood into hepatocytes. The amino acid sequence of OATP1B3 is 80% identical to that of OATP1B1 and the two transporters have common as well as distinct substrates. At low concentrations, estrone-3-sulfate is preferentially transported by OATP1B1, while cholecystokinin octapeptide (CCK-8) is a specific substrate for OATP1B3. To determine which domains are important for the substrate selectivity of OATP1B1 and 1B3, we constructed a series of chimeric proteins between OATP1B1 and 1B3. These chimeras were transiently expressed in human embryonic kidney cells (HEK293), uptake of estrone-3-sulfate and CCK-8 was measured and protein surface expression was determined. Our results showed that transmembrane domain 10 is critical for the substrate selectivity of both OATP1B1 and 1B3.

报告人简介：

贵春山， 男，1979年生。2000年毕业于四川大学，2005年毕业于中科院上海药物研究所获博士学位，同年开始在美国堪萨斯大学医学中心做博士后研究。

近期主要论文：

1. Gui C, Obaidat A, Chaguturu R, Hagenbuch B. Development of a cell-based high-throughput assay to screen for inhibitors of organic anion transporting polypeptides 1B1 and 1B3. Curr. Chem. Genomics 2010, 4:1-8.

2. Gui C, Hagenbuch B. Cloning/characterization of the canine organic anion transporting polypeptide 1b4 (Oatp1b4) and classification of the canine OATP/SLCO members. Comp. Biochem. Physiol. 2010, 151:393-399.

3. Gui C, Hagenbuch B. Role of transmembrane domain 10 for the function of organic anion transporting polypeptide 1B1. Protein Sci. 2009, 18:2298-2306.

4. Gui C, Wahlgren B, Lushington GH, Hagenbuch B. Identification, Ki determination and CoMFA analysis of nuclear receptor ligands as competitive inhibitors of OATP1B1-mediated estradiol-17β-glucuronide transport. Pharmacol. Res. 2009, 60:50-56.

5. Gui C, Hagenbuch B. Amino acid residues in transmembrane domain 10 of organic anion transporting polypeptide 1B3 are critical for cholecystokinin octapeptide transport. Biochemistry 2008, 47:9090-9097.

6. Gui C, Miao Y, Thompson L, Wahlgren B, Mock M, Stieger B, Hagenbuch B. Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3. Eur. J. Pharmacol. 2008, 584:57-65.

7. B. Hagenbuch, C. Gui. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 2008, 38:778-801.

8. Gui C, Zhu W, Chen G, Luo X, Liew OW, Puah CM, Chen K, Jiang H. Understanding the regulation mechanisms of PAF receptor by agonists and antagonists: molecular modeling and molecular dynamics simulation studies. Proteins 2007, 67:41-52.