3ROP: Crystal Structure Of Human Cd38 In Complex With Compound Cz-50b

Citation:
Abstract
CD38 is a signaling enzyme responsible for catalyzing the synthesis of cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate; both are universal Ca(2+) messenger molecules. Ablation of the CD38 gene in mice causes multiple physiological defects, including impaired oxytocin release, that result in altered social behavior. A series of catalysis-based inhibitors of CD38 were designed and synthesized, starting with arabinosyl-2'-fluoro-2'-deoxynicotinamide mononucleotide. Structure-function relationships were analyzed to assess the structural determinants important for inhibiting the NADase activity of CD38. X-ray crystallography was used to reveal the covalent intermediates that were formed with the catalytic residue, Glu226. Metabolically stable analogues that were resistant to inactivation by phosphatase and esterase were synthesized and shown to be effective in inhibiting intracellular cADPR production in human HL-60 cells during induction of differentiation by retinoic acid. The inhibition was species-independent, and the analogues were similarly effective in blocking the cyclization reaction of CD38 in rat ventricular tissue extracts, as well as inhibiting the alpha-agonist-induced constriction in rat mesentery arteries. These compounds thus represent the first generally applicable and catalysis-based inhibitors of the Ca(2+) signaling function of CD38.
PDB ID: 3ROPDownload
MMDB ID: 96053
PDB Deposition Date: 2011/4/26
Updated in MMDB: 2011/12
Experimental Method:
x-ray diffraction
Resolution: 1.94  Å
Source Organism:
Similar Structures:
Biological Unit for 3ROP: monomeric; determined by author and by software (PISA)
Molecular Components in 3ROP
Label Count Molecule
Protein (1 molecule)
1
Adp-ribosyl Cyclase 1(Gene symbol: CD38)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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