title: Crystal structure of visfatin/pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866.
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.
authors.affiliation: Department of Life Science, Gwangju Institute of Science & Technology, Gwangju 500-712, Korea.
authors.forename: Mun-Kyoung
authors.initials: MK
authors.lastname: Kim
authors.forename: Jun Hyuck
authors.initials: JH
authors.lastname: Lee
authors.forename: Hun
authors.initials: H
authors.lastname: Kim
authors.forename: Soo Jeong
authors.initials: SJ
authors.lastname: Park
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Gil Bu
authors.initials: GB
authors.lastname: Kang
authors.forename: Yun Sok
authors.initials: YS
authors.lastname: Lee
authors.forename: Jae Bum
authors.initials: JB
authors.lastname: Kim
authors.forename: Kyeong Kyu
authors.initials: KK
authors.lastname: Kim
authors.forename: Se Won
authors.initials: SW
authors.lastname: Suh
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Eom
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000737:chemistry; D019281:Dimerization; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009537:Nicotinamide Mononucleotide / Q000737:chemistry; D054409:Nicotinamide Phosphoribosyltransferase; D010880:Piperidines / Q000737:chemistry*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D051381:Rats; D017385:Sequence Homology
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D016207:Cytokines; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D009537:Nicotinamide Mononucleotide; D054409:Nicotinamide Phosphoribosyltransferase; C504970:nicotinamide phosphoribosyltransferase, rat