7Q8T

Crystal structure of NAMPT bound to ligand TSY535(compound 9a)

7Q8T の概要

• エントリーDOI: 10.2210/pdb7q8t/pdb
• 分子名称: Nicotinamide phosphoribosyltransferase, [(2~{R},3~{S},4~{R},5~{S})-3,4-bis(oxidanyl)-5-[4-[[[4-(phenylsulfonyl)phenyl]carbamoylamino]methyl]phenyl]oxolan-2-yl]methyl dihydrogen phosphate, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, activator, structural genomics, structural genomics consortium, sgc, transferase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 113653.91

構造登録者

Kraemer, A.,Tang, S.,Butterworth, S.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2021-11-11, 公開日: 2021-11-24, 最終更新日: 2024-01-31)

主引用文献

Tang, S.,Garzon Sanz, M.,Smith, O.,Kramer, A.,Egbase, D.,Caton, P.W.,Knapp, S.,Butterworth, S.
Chemistry-led investigations into the mode of action of NAMPT activators, resulting in the discovery of non-pyridyl class NAMPT activators.
Acta Pharm Sin B, 13:709-721, 2023

PubMed Abstract: The cofactor nicotinamide adenine dinucleotide (NAD) plays a key role in a wide range of physiological processes and maintaining or enhancing NAD levels is an established approach to enhancing healthy aging. Recently, several classes of nicotinamide phosphoribosyl transferase (NAMPT) activators have been shown to increase NAD levels and and to demonstrate beneficial effects in animal models. The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors, however the basis for the switch from inhibitory activity to activation is not well understood. Here we report an evaluation of the structure activity relationships of NAMPT activators by designing, synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators. The results of these studies led us to hypothesise that these activators act a through-water interaction in the NAMPT active site, resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead, which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.

PubMed: 36873168
DOI: 10.1016/j.apsb.2022.07.016

実験手法

X-RAY DIFFRACTION (2.15 Å)