2i65
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Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis
OverviewOverview
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 StructureAbout this Structure
2I65 is a Single protein structure of sequence from Homo sapiens with NAD as ligand. Active as NAD(+) nucleosidase, with EC number 3.2.2.5 Full crystallographic information is available from OCA.
ReferenceReference
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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