Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules

Yun Shi, Philip S. Kerry, Jeffrey D. Nanson, Todd Bosanac, Yo Sasaki, Raul Krauss, Forhad K. Saikot, Sarah E. Adams, Tamim Mosaiab, Veronika Masic, Xianrong Mao, Faith Rose, Eduardo Vasquez, Marieke Furrer, Katie Cunnea, Andrew Brearley, Weixi Gu, Zhenyao Luo, Lou Brillault, Michael J. LandsbergAaron DiAntonio, Bostjan Kobe, Jeffrey Milbrandt, Robert O. Hughes, Thomas Ve

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Pages (from-to)1643-1659.e10
JournalMolecular cell
Volume82
Issue number9
DOIs
StatePublished - May 5 2022

Keywords

  • ARM domain
  • NADase
  • TIR domain
  • X-ray crystallography
  • allosteric activator
  • base exchange
  • cryo-EM
  • orthosteric inhibitor

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