9CR4

CryoEM Structure of the C-terminally truncated form of human NAD Kinase

Summary for 9CR4

• Entry DOI: 10.2210/pdb9cr4/pdb
• EMDB information: 45831 45832 45856
• Descriptor: NAD kinase (1 entity in total)
• Functional Keywords: catalyzes the reaction of atp + nad+ = adp + h+ + nadp+, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 164279.64

Authors

Li, Y.,Chen, Z.,Mary, C.,Labesse, G.,Hoxhaj, G. (deposition date: 2024-07-20, release date: 2025-01-08, Last modification date: 2025-02-12)

Primary citation

Praharaj, P.P.,Li, Y.,Mary, C.,Soflaee, M.H.,Ryu, K.,Kim, D.,Tran, D.H.,Dey, T.,Tom, H.J.,Rion, H.,Gelin, M.,Lemoff, A.,Zacharias, L.G.,Patricio, J.S.,Mathews, T.P.,Chen, Z.,Lionne, C.,Hoxhaj, G.,Labesse, G.
Cryo-EM structure and regulation of human NAD kinase.
Sci Adv, 11:eads2664-eads2664, 2025

PubMed Abstract: Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is a crucial reducing cofactor for reductive biosynthesis and protection from oxidative stress. To fulfill their heightened anabolic and reductive power demands, cancer cells must boost their NADPH production. Progrowth and mitogenic protein kinases promote the activity of cytosolic NAD kinase (NADK), which produces NADP, a limiting NADPH precursor. However, the molecular architecture and mechanistic regulation of human NADK remain undescribed. Here, we report the cryo-electron microscopy structure of human NADK, both in its apo-form and in complex with its substrate NAD (nicotinamide adenine dinucleotide), revealing a tetrameric organization with distinct structural features. We discover that the amino (N)- and carboxyl (C)-terminal tails of NADK have opposing effects on its enzymatic activity and cellular NADP(H) levels. Specifically, the C-terminal region is critical for NADK activity, whereas the N-terminal region exhibits an inhibitory role. This study highlights molecular insights into the regulation of a vital enzyme governing NADP(H) production.

PubMed: 39854463
DOI: 10.1126/sciadv.ads2664

Experimental method

ELECTRON MICROSCOPY (2.81 Å)