7RTC

Crystal structure of the ARM domain from Drosophila SARM1 in complex with NaMN

7RTC の概要

• エントリーDOI: 10.2210/pdb7rtc/pdb
• 分子名称: NAD(+) hydrolase sarm1, NICOTINATE MONONUCLEOTIDE (2 entities in total)
• 機能のキーワード: axon degeneration, arm domain, inhibitor, hydrolase
• 由来する生物種: Drosophila melanogaster (Fruit fly)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 121418.55

構造登録者

Gu, W.,Ve, T.,Kobe, B. (登録日: 2021-08-13, 公開日: 2021-09-01, 最終更新日: 2024-10-23)

主引用文献

Sasaki, Y.,Zhu, J.,Shi, Y.,Gu, W.,Kobe, B.,Ve, T.,DiAntonio, A.,Milbrandt, J.
Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection.
Exp Neurol, 345:113842-113842, 2021

PubMed Abstract: SARM1 is an inducible NAD hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site within the SARM1 N-terminal ARM domain. In healthy neurons with abundant NAD, binding of NAD blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD hydrolase. Hence, NAD metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD hydrolase. This dual upstream and downstream role for NAD metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD precursor nicotinic acid mononucleotide (NaMN). We show that NaMN inhibits SARM1 activation, and demonstrate that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Analysis of the NaMN-ARM domain co-crystal structure shows that NaMN competes with NMN for binding to the SARM1 allosteric site and promotes the open, autoinhibited configuration of SARM1 ARM domain. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD, and NaMN to monitor cellular NAD homeostasis and regulate SARM1 NAD hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders.

PubMed: 34403688
DOI: 10.1016/j.expneurol.2021.113842

実験手法

X-RAY DIFFRACTION (3.31 Å)