7ENQ

Crystal structure of human NAMPT in complex with compound NAT

7ENQ の概要

• エントリーDOI: 10.2210/pdb7enq/pdb
• 分子名称: Nicotinamide phosphoribosyltransferase, 2-(2-~{tert}-butylphenoxy)-~{N}-(4-hydroxyphenyl)ethanamide, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: nampt, nat, nad, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 227462.52

構造登録者

Wang, G.,Wu, C.,Liu, M.,Yao, H.,Li, C.,Wang, L.,Tang, Y. (登録日: 2021-04-19, 公開日: 2022-05-04, 最終更新日: 2023-11-29)

主引用文献

Yao, H.,Liu, M.,Wang, L.,Zu, Y.,Wu, C.,Li, C.,Zhang, R.,Lu, H.,Li, F.,Xi, S.,Chen, S.,Gu, X.,Liu, T.,Cai, J.,Wang, S.,Yang, M.,Xing, G.G.,Xiong, W.,Hua, L.,Tang, Y.,Wang, G.
Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity.
Cell Res., 32:570-584, 2022

PubMed Abstract: The decline of nicotinamide adenine dinucleotide (NAD) occurs in a variety of human pathologies including neurodegeneration. NAD-boosting agents can provide neuroprotective benefits. Here, we report the discovery and development of a class of potent activators (NATs) of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway. We obtained the crystal structure of NAMPT in complex with the NAT, which defined the allosteric action of NAT near the enzyme active site. The optimization of NAT further revealed the critical role of K189 residue in boosting NAMPT activity. NATs effectively increased intracellular levels of NAD and induced subsequent metabolic and transcriptional reprogramming. Importantly, NATs exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any overt toxicity. These findings demonstrate the potential of NATs in the treatment of neurodegenerative diseases or conditions associated with NAD level decline.

PubMed: 35459935
DOI: 10.1038/s41422-022-00651-9

実験手法

X-RAY DIFFRACTION (2.20496616708 Å)