8TM7
Human NAMPT in complex with substrate NAM and small molecule activator NP-A3
Summary for 8TM7
| Entry DOI | 10.2210/pdb8tm7/pdb |
| Descriptor | Nicotinamide phosphoribosyltransferase, GLYCEROL, NICOTINAMIDE, ... (7 entities in total) |
| Functional Keywords | nad+ aging enzyme activation, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 114883.99 |
| Authors | |
| Primary citation | 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 Cited by 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: 38352833DOI: 10.1021/acsmedchemlett.3c00391 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.79 Å) |
Structure validation
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