7NAG

Crystal structure of the TIR domain from human SARM1 in complex with 1AD

7NAG の概要

• エントリーDOI: 10.2210/pdb7nag/pdb
• 分子名称: Sterile alpha and TIR motif-containing protein 1, [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-5-(5-iodanylisoquinolin-2-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate (3 entities in total)
• 機能のキーワード: nadase, axon degeneration, hydrolase
• 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: 34262.13

構造登録者

Shi, Y.,Bosanac, T.,Hughes, R.O.,Ve, T. (登録日: 2021-06-21, 公開日: 2022-03-23, 最終更新日: 2023-10-18)

主引用文献

Shi, Y.,Kerry, P.S.,Nanson, J.D.,Bosanac, T.,Sasaki, Y.,Krauss, R.,Saikot, F.K.,Adams, S.E.,Mosaiab, T.,Masic, V.,Mao, X.,Rose, F.,Vasquez, E.,Furrer, M.,Cunnea, K.,Brearley, A.,Gu, W.,Luo, Z.,Brillault, L.,Landsberg, M.J.,DiAntonio, A.,Kobe, B.,Milbrandt, J.,Hughes, R.O.,Ve, T.
Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules.
Mol.Cell, 82:1643-, 2022

PubMed Abstract: The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD mimetics and the allosteric activator nicotinamide mononucleotide (NMN). NMN binding triggers reorientation of the armadillo repeat (ARM) domains, which disrupts ARM:TIR interactions and leads to formation of a two-stranded TIR domain assembly. The active site spans two molecules in these assemblies, explaining the requirement of TIR domain self-association for NADase activity and axon degeneration. Our results reveal the mechanisms of SARM1 activation and substrate binding, providing rational avenues for the design of new therapeutics targeting SARM1.

PubMed: 35334231
DOI: 10.1016/j.molcel.2022.03.007

実験手法

X-RAY DIFFRACTION (1.72 Å)