2i66
From Proteopedia
| |||||||
| , resolution 1.70Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Gene: | CD38 (Homo sapiens) | ||||||
| Activity: | NAD(+) nucleosidase, with EC number 3.2.2.5 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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. 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
Page seeded by OCA on Thu Mar 20 17:25:54 2008
