Crystal structure of visfatin/pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866 |
| |
Authors: | Kim Mun-Kyoung Lee Jun Hyuck Kim Hun Park Soo Jeong Kim Sung Hyun Kang Gil Bu Lee Yun Sok Kim Jae Bum Kim Kyeong Kyu Suh Se Won Eom Soo Hyun |
| |
Institution: | 1 Department of Life Science, Gwangju Institute of Science & Technology, Gwangju 500-712, Korea 2 Department of Molecular Cell Biology, Center for Molecular Medicine, SBRI, Sungkyunkwan University, School of Medicine, Suwon, Korea 3 Departments of Chemistry and Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea |
| |
Abstract: | Visfatin/pre-B cell colony-enhancing factor 1 (PBEF)/nicotinamide phosphoribosyltransferase (NAmPRTase) is a multifunctional protein having phosphoribosyltransferase, cytokine and adipokine activities. Originally isolated as a cytokine promoting the differentiation of B cell precursors, it was recently suggested to act as an insulin analog via the insulin receptor. Here, we describe the first crystal structure of visfatin in three different forms: apo and in complex with either nicotinamide mononucleotide (NMN) or the NAmPRTase inhibitor FK-866 which was developed as an anti-cancer agent, interferes with NAD biosynthesis, showing a particularly high specificity for NAmPRTase. The crystal structures of the complexes with either NMN or FK-866 show that the enzymatic active site of visfatin is optimized for nicotinamide binding and that the nicotinamide-binding site is important for inhibition by FK-866. Interestingly, visfatin mimics insulin signaling by binding to the insulin receptor with an affinity similar to that of insulin and does not share the binding site with insulin on the insulin receptor. To predict binding sites, the potential interaction patches of visfatin and the L1-CR-L2 domain of insulin receptor were generated and analyzed. Although the relationship between the insulin-mimetic property and the enzymatic function of visfatin has not been clearly established, our structures raise the intriguing possibility that the glucose metabolism and the NAD biosynthesis are linked by visfatin. |
| |
Keywords: | PBEF pre-B cell colony-enhancing factor 1 PRTase phosphoribosyltransferase ITC isothermal titration calorimetry NAmPRTase nicotinamide phosphoribosyltransferase PRPP phosphoribosyl pyrophosphate MAD multiwavelength anomalous dispersion QA quinolinic acid NA nicotinate |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|