Researchers at Children’s Medical Center Research Institute at UT Southwestern (CRI) and the Centre de Biologie Structurale (CBS) at the Université of Montpellier in France have solved the high-resolution structure of human NAD kinase (NADK) using cryo-electron microscopy (cryo-EM), enabling visualization of NADK in near-atomic detail.
Gerta Hoxhaj, Ph.D., Assistant Professor in CRI and of Biochemistry and Pediatrics.
Led by Gerta Hoxhaj, Ph.D., Assistant Professor in CRI and of Biochemistry and Pediatrics, along with Gilles Labesse, Ph.D., Research Director at CBS, the study published in Science Advances reveals that NADK — a crucial enzyme that fuels cancer cell metabolism by regulating NADPH production — adopts a tetrameric architecture and is tightly controlled by its N- and C-terminal extensions, which act as opposing regulatory elements.
By mapping NADK structures in both its apo-state (unbound) and the state when bound to its substrate NAD+, the team uncovered mechanistic insights into how the enzyme is activated. This discovery paves the way to develop targeted NADK inhibitors for potential cancer therapies. The findings also establish a structural framework for understanding NADK’s role in redox balance in cancer cells.
This new research builds upon Drs. Hoxhaj’s and Labesse’s previous 2022 study published in Molecular Cell that shows the crystal structure of human NADK2 reveals a dimeric organization and active site occlusion by lysine acetylation.
