Crystal structure of visfatin/pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866.
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.
Kim
Mun-Kyoung
MK
Department of Life Science, Gwangju Institute of Science & Technology, Gwangju 500-712, Korea.
Lee
Jun Hyuck
JH
Kim
Hun
H
Park
Soo Jeong
SJ
Kim
Sung Hyun
SH
Kang
Gil Bu
GB
Lee
Yun Sok
YS
Kim
Jae Bum
JB
Kim
Kyeong Kyu
KK
Suh
Se Won
SW
Eom
Soo Hyun
SH
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
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