3OFS: Dynamic conformations of the CD38-mediated NAD cyclization captured using multi-copy crystallography

Citation:
Abstract
The extracellular domain of human CD38 is a multifunctional enzyme involved in the metabolism of two Ca(2+) messengers: cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate. When NAD is used as substrate, CD38 predominantly hydrolyzes it to ADP-ribose, with a trace amount of cyclic ADP-ribose produced through cyclization of the substrate. However, mutation of a key residue at the active site, E146, inhibits the hydrolysis activity of CD38 but greatly increases its cyclization activity. To understand the role of the residue E146 in the catalytic process, we determined the crystal structure of the E146A mutant protein with a substrate analogue, arabinosyl-2'-fluoro-deoxy-nicotinamide adenine dinucleotide. The structure captured the enzymatic reaction intermediates in six different conformations in a crystallographic asymmetric unit. The structural results indicate a folding-back process for the adenine ring of the substrate and provide the first multiple snapshots of the process. Our approach of utilizing multiple molecules in the crystallographic asymmetric unit should be generally applicable for capturing the dynamic nature of enzymatic catalysis.
PDB ID: 3OFSDownload
MMDB ID: 87355
PDB Deposition Date: 2010/8/16
Updated in MMDB: 2010/12
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Similar Structures:
Biological Unit for 3OFS: monomeric; determined by author and by software (PISA)
Molecular Components in 3OFS
Label Count Molecule
Protein (1 molecule)
1
Adp-ribosyl Cyclase 1(Gene symbol: CD38)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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