2i66
From Proteopedia
(New page: 200px<br /> <applet load="2i66" size="450" color="white" frame="true" align="right" spinBox="true" caption="2i66, resolution 1.70Å" /> '''Structural Basis fo...) |
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| - | [[Image:2i66.gif|left|200px]]<br /> | + | [[Image:2i66.gif|left|200px]]<br /><applet load="2i66" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="2i66, resolution 1.70Å" /> | caption="2i66, resolution 1.70Å" /> | ||
'''Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis'''<br /> | '''Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The enzymatic cleavage of the nicotinamide-glycosidic bond on nicotinamide | + | The enzymatic cleavage of the nicotinamide-glycosidic bond on nicotinamide adenine dinucleotide (NAD(+)) has been proposed to go through an oxocarbenium ion-like transition state. Because of the instability of the ionic intermediate, there has been no structural report on such a transient reactive species. Human CD38 is an ectoenzyme that can use NAD(+) to synthesize two calcium-mobilizing molecules. By using NAD(+) and a surrogate substrate, NGD(+), we captured and determined crystal structures of the enzyme complexed with an intermediate, a substrate, and a product along the reaction pathway. Our results showed that the intermediate is stabilized by polar interactions with the catalytic residue Glu(226) rather than by a covalent linkage. The polar interactions between Glu(226) and the substrate 2',3'-OH groups are essential for initiating catalysis. Ser(193) was demonstrated to have a regulative role during catalysis and is likely to be involved in intermediate stabilization. In addition, a product inhibition effect by ADP-ribose (through the reorientation of the product) or GDP-ribose (through the formation of a covalently linked GDP-ribose dimer) was observed. These structural data provide insights into the understanding of multiple catalysis and clues for drug design. |
==About this Structure== | ==About this Structure== | ||
| - | 2I66 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with G1R and G2R as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/NAD(+)_nucleosidase NAD(+) nucleosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.2.5 3.2.2.5] Full crystallographic information is available from [http:// | + | 2I66 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=G1R:'>G1R</scene> and <scene name='pdbligand=G2R:'>G2R</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/NAD(+)_nucleosidase NAD(+) nucleosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.2.5 3.2.2.5] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I66 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Graeff, R.]] | [[Category: Graeff, R.]] | ||
[[Category: Hao, Q.]] | [[Category: Hao, Q.]] | ||
| - | [[Category: Kriksunov, I | + | [[Category: Kriksunov, I A.]] |
| - | [[Category: Lee, H | + | [[Category: Lee, H C.]] |
[[Category: Liu, Q.]] | [[Category: Liu, Q.]] | ||
[[Category: Munshi, C.]] | [[Category: Munshi, C.]] | ||
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[[Category: the catalytic pocket]] | [[Category: the catalytic pocket]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:49:28 2008'' |
Revision as of 15:49, 21 February 2008
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Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis
Overview
The enzymatic cleavage of the nicotinamide-glycosidic bond on nicotinamide adenine dinucleotide (NAD(+)) has been proposed to go through an oxocarbenium ion-like transition state. Because of the instability of the ionic intermediate, there has been no structural report on such a transient reactive species. Human CD38 is an ectoenzyme that can use NAD(+) to synthesize two calcium-mobilizing molecules. By using NAD(+) and a surrogate substrate, NGD(+), we captured and determined crystal structures of the enzyme complexed with an intermediate, a substrate, and a product along the reaction pathway. Our results showed that the intermediate is stabilized by polar interactions with the catalytic residue Glu(226) rather than by a covalent linkage. The polar interactions between Glu(226) and the substrate 2',3'-OH groups are essential for initiating catalysis. Ser(193) was demonstrated to have a regulative role during catalysis and is likely to be involved in intermediate stabilization. In addition, a product inhibition effect by ADP-ribose (through the reorientation of the product) or GDP-ribose (through the formation of a covalently linked GDP-ribose dimer) was observed. These structural data provide insights into the understanding of multiple catalysis and clues for drug design.
About this Structure
2I66 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as NAD(+) nucleosidase, with EC number 3.2.2.5 Full crystallographic information is available from OCA.
Reference
Structural basis for the mechanistic understanding of human CD38-controlled multiple catalysis., Liu Q, Kriksunov IA, Graeff R, Munshi C, Lee HC, Hao Q, J Biol Chem. 2006 Oct 27;281(43):32861-9. Epub 2006 Sep 2. PMID:16951430
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