8TM7

Human NAMPT in complex with substrate NAM and small molecule activator NP-A3

8TM7 の概要

• エントリーDOI: 10.2210/pdb8tm7/pdb
• 分子名称: Nicotinamide phosphoribosyltransferase, GLYCEROL, NICOTINAMIDE, ... (7 entities in total)
• 機能のキーワード: nad+ aging enzyme activation, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 114883.99

構造登録者

Ratia, K.M.,Thatcher, G.R. (登録日: 2023-07-28, 公開日: 2024-06-12)

主引用文献

Gordon-Blake, J.,Ratia, K.,Weidig, V.,Velma, G.R.,Ackerman-Berrier, M.,Penton, C.,Musku, S.R.,Alves, E.T.M.,Driver, T.,Tai, L.,Thatcher, G.R.J.
Nicotinamide Phosphoribosyltransferase Positive Allosteric Modulators Attenuate Neuronal Oxidative Stress.
Acs Med.Chem.Lett., 15:205-214, 2024

PubMed Abstract: Evidence supports boosting nicotinamide adenine dinucleotide (NAD) to counteract oxidative stress in aging and neurodegenerative disease. One approach is to enhance the activity of nicotinamide phosphoribosyltransferase (NAMPT). Novel NAMPT positive allosteric modulators (N-PAMs) were identified. A cocrystal structure confirmed N-PAM binding to the NAMPT rear channel. Early hit-to-lead efforts led to a 1.88-fold maximum increase in the level of NAD in human THP-1 cells. Select N-PAMs were assessed for mitigation of reactive oxygen species (ROS) in HT-22 neuronal cells subject to inflammatory stress using tumor necrosis factor alpha (TNFα). N-PAMs that increased NAD more effectively in THP-1 cells attenuated TNFα-induced ROS more effectively in HT-22 cells. The most efficacious N-PAM completely attenuated ROS elevation in glutamate-stressed HT-22 cells, a model of neuronal excitotoxicity. This work demonstrates for the first time that N-PAMs are capable of mitigating elevated ROS in neurons stressed with TNFα and glutamate and provides support for further N-PAM optimization for treatment of neurodegenerative diseases.

PubMed: 38352833
DOI: 10.1021/acsmedchemlett.3c00391

実験手法

X-RAY DIFFRACTION (1.79 Å)