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TitleA duplex structure of SARM1 octamers stabilized by a new inhibitor.
Journal, issue, pagesCell Mol Life Sci, Vol. 80, Issue 1, Page 16, Year 2022
Publish dateDec 23, 2022
AuthorsTami Khazma / Yarden Golan-Vaishenker / Julia Guez-Haddad / Atira Grossman / Radhika Sain / Michal Weitman / Alexander Plotnikov / Ran Zalk / Avraham Yaron / Michael Hons / Yarden Opatowsky /
PubMed AbstractIn recent years, there has been growing interest in SARM1 as a potential breakthrough drug target for treating various pathologies of axon degeneration. SARM1-mediated axon degeneration relies on its ...In recent years, there has been growing interest in SARM1 as a potential breakthrough drug target for treating various pathologies of axon degeneration. SARM1-mediated axon degeneration relies on its TIR domain NADase activity, but recent structural data suggest that the non-catalytic ARM domain could also serve as a pharmacological site as it has an allosteric inhibitory function. Here, we screened for synthetic small molecules that inhibit SARM1, and tested a selected set of these compounds in a DRG axon degeneration assay. Using cryo-EM, we found that one of the newly discovered inhibitors, a calmidazolium designated TK106, not only stabilizes the previously reported inhibited conformation of the octamer, but also a meta-stable structure: a duplex of octamers (16 protomers), which we have now determined to 4.0 Å resolution. In the duplex, each ARM domain protomer is engaged in lateral interactions with neighboring protomers, and is further stabilized by contralateral contacts with the opposing octamer ring. Mutagenesis of the duplex contact sites leads to a moderate increase in SARM1 activation in cultured cells. Based on our data we propose that the duplex assembly constitutes an additional auto-inhibition mechanism that tightly prevents pre-mature activation and axon degeneration.
External linksCell Mol Life Sci / PubMed:36564647 / PubMed Central
MethodsEM (single particle)
Resolution4.02 Å
Structure data

13951

7qg0

EMDB-13951, PDB-7qg0:
Inhibitor-induced hSARM1 duplex
Method: EM (single particle) / Resolution: 4.02 Å

Source
  • homo sapiens (human)
KeywordsAPOPTOSIS / SARM1 / inhibitor / axon / degeneration

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