2g97: Difference between revisions

Revision as of 18:29, 21 February 2008

Crystal Structure of Visfatin/Pre-B Cell Colony Enhancing Factor 1/Nicotinamide Phosphoribosyltransferase In Complex with the Specific Inhibitor FK-866

OverviewOverview

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.

About this StructureAbout this Structure

2G97 is a Single protein structure of sequence from Rattus norvegicus with as ligand. Active as Nicotinamide phosphoribosyltransferase, with EC number 2.4.2.12 Full crystallographic information is available from OCA.

ReferenceReference

Crystal structure of visfatin/pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866., Kim MK, Lee JH, Kim H, Park SJ, Kim SH, Kang GB, Lee YS, Kim JB, Kim KK, Suh SW, Eom SH, J Mol Biol. 2006 Sep 8;362(1):66-77. Epub 2006 Aug 9. PMID:16901503

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-[[Image:2g97.gif|left|200px]]<br /><applet load="2g97" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:2g97.gif|left|200px]]<br /><applet load="2g97" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="2g97, resolution 2.9&Aring;" />
 '''Crystal Structure of Visfatin/Pre-B Cell Colony Enhancing Factor 1/Nicotinamide Phosphoribosyltransferase In Complex with the Specific Inhibitor FK-866'''<br />
 ==Overview==
-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.
+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.
 ==About this Structure==
-G97 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with DGB as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Nicotinamide_phosphoribosyltransferase Nicotinamide phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.12 2.4.2.12] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2G97 OCA].
+G97 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=DGB:'>DGB</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Nicotinamide_phosphoribosyltransferase Nicotinamide phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.12 2.4.2.12] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G97 OCA].
 ==Reference==
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 [[Category: Rattus norvegicus]]
 [[Category: Single protein]]
-[[Category: Eom, S.H.]]
+[[Category: Eom, S H.]]
-[[Category: Kim, M.K.]]
+[[Category: Kim, M K.]]
 [[Category: DGB]]
 [[Category: fk-866]]
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 [[Category: visfatin]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 11:02:58 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:29:22 2008''