| Literature DB >> 35334231 |
Yun Shi1, Philip S Kerry2, Jeffrey D Nanson3, Todd Bosanac4, Yo Sasaki5, Raul Krauss4, Forhad K Saikot3, Sarah E Adams2, Tamim Mosaiab1, Veronika Masic1, Xianrong Mao5, Faith Rose1, Eduardo Vasquez1, Marieke Furrer6, Katie Cunnea2, Andrew Brearley2, Weixi Gu3, Zhenyao Luo3, Lou Brillault7, Michael J Landsberg3, Aaron DiAntonio8, Bostjan Kobe3, Jeffrey Milbrandt5, Robert O Hughes9, Thomas Ve10.
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.Entities:
Keywords: ARM domain; NADase; TIR domain; X-ray crystallography; allosteric activator; base exchange; cryo-EM; orthosteric inhibitor
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Year: 2022 PMID： 35334231 PMCID： PMC9188649 DOI： 10.1016/j.molcel.2022.03.007
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 19.328