8VAU

Nicotinamide Riboside and CD38: Covalent Inhibition and Live-Cell Labeling

Summary for 8VAU

• Entry DOI: 10.2210/pdb8vau/pdb
• Descriptor: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1, Nicotinamide riboside, alpha-D-ribofuranose, ... (4 entities in total)
• Functional Keywords: nicotinamide riboside, cd38, nucleoside, inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 60338.23

Authors

Kao, G.,Zhang, X.N.,Nasertorabi, F.,Katz, B.B.,Li, Z.,Dai, Z.,Zhang, Z.,Zhang, L.,Louie, S.G.,Cherezov, V.,Zhang, Y. (deposition date: 2023-12-11, release date: 2024-11-06, Last modification date: 2024-12-11)

Primary citation

Kao, G.,Zhang, X.N.,Nasertorabi, F.,Katz, B.B.,Li, Z.,Dai, Z.,Zhang, Z.,Zhang, L.,Louie, S.G.,Cherezov, V.,Zhang, Y.
Nicotinamide Riboside and CD38: Covalent Inhibition and Live-Cell Labeling.
Jacs Au, 4:4345-4360, 2024

PubMed Abstract: Nicotinamide adenine dinucleotide (NAD) is required for a myriad of metabolic, signaling, and post-translational events in cells. Its levels in tissues and organs are closely associated with health conditions. The homeostasis of NAD is regulated by biosynthetic pathways and consuming enzymes. As a membrane-bound protein with robust NAD hydrolase activity, cluster of differentiation 38 (CD38) is a major degrader of NAD. Deficiency or inhibition of CD38 enhances NAD levels in vivo, resulting in various therapeutic benefits. As a metabolic precursor of NAD, nicotinamide mononucleotide can be rapidly hydrolyzed by CD38, whereas nicotinamide riboside (NR) lacks CD38 substrate activity. Given their structural similarities, we explored the inhibition potential of NR. To our surprise, NR exhibits marked inhibitory activity against CD38 by forming a stable ribosyl-ester bond with the glutamate residue 226 at the active site. Inspired by this discovery, we designed and synthesized a clickable NR featuring an azido substitution at the 5'-OH position. This cell-permeable NR analogue enables covalent labeling and imaging of both extracellular and intracellular CD38 in live cells. Our work discovers an unrecognized molecular function of NR and generates a covalent probe for health-related CD38. These findings offer new insights into the role of NR in modulating NAD metabolism and CD38-mediated signaling as well as an innovative tool for in-depth studies of CD38 in physiology and pathophysiology.

PubMed: 39610739
DOI: 10.1021/jacsau.4c00695

Experimental method

X-RAY DIFFRACTION (2.1 Å)