@article{c3ce083710c54697915a5fbae1b20ae2,
title = "Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules",
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.",
keywords = "ARM domain, NADase, TIR domain, X-ray crystallography, allosteric activator, base exchange, cryo-EM, orthosteric inhibitor",
author = "Yun Shi and Kerry, {Philip S.} and Nanson, {Jeffrey D.} and Todd Bosanac and Yo Sasaki and Raul Krauss and Saikot, {Forhad K.} and Adams, {Sarah E.} and Tamim Mosaiab and Veronika Masic and Xianrong Mao and Faith Rose and Eduardo Vasquez and Marieke Furrer and Katie Cunnea and Andrew Brearley and Weixi Gu and Zhenyao Luo and Lou Brillault and Landsberg, {Michael J.} and Aaron DiAntonio and Bostjan Kobe and Jeffrey Milbrandt and Hughes, {Robert O.} and Thomas Ve",
note = "Funding Information: We acknowledge use of the Australian Synchrotron MX facility and thank the staff for their support. We acknowledge the support and use of the Krios at the Midlands Regional Cryo-EM Facility, Institute of Structural and Chemical Biology, University of Leicester, UK. We also acknowledge the Centre for Microscopy and Microanalysis, University of Queensland and staff (Bill Close, Matthias Floetenmeyer, Richard Webb and Roger Wepf). The work was supported by the National Health and Medical Research Council (NHMRC grants 1196590 to T.V. 1107804 and 1160570 to B.K. and T.V. 1071659 to B.K. and 1108859 to T.V.), the Australian Research Council (ARC) Future Fellowship (FT200100572) to T.V. the ARC Laureate Fellowship (FL180100109) to B.K. the National Institutes of Health (R01NS087632 to J.M. and A.D.) and Disarm Therapeutics. T.V. received ARC DECRA (DE170100783) funding. Y.Shi was a recipient of Griffith University Postdoctoral Fellowship Scheme. F.K.S. was supported by the University of Queensland Research Training Scholarship. Conceptualization, T.V. Y. Shi, R.O.H. B.K.; Investigation, T.V. Y. Shi, P.S.K. J.D.N. T.B. Y. Sasaki, R.K. F.K.S. S.E.A. T.M. V.M. X.M. F.R. E.V. M.F. K.C. W.G. Z.L. L.B. M.J.L.; Writing – original draft, T.V. Y. Shi; Writing – review & editing, all authors; Funding acquisition, T.V. R.O.H. B.K.; Resources, T.V. B.K. R.O.H. J.M. A.D.; Supervision, T.V. R.O.H. B.K. J.M. A.D. A.B. A.D. and J.M. are co-founders, scientific advisory board members, and shareholders of Disarm Therapeutics. B.K. is a shareholder of Disarm Therapeutics. Y. Sasaki and B.K. are consultants to Disarm Therapeutics. B.K. and T.V. receive research funding from Disarm Therapeutics. R.O.H. R.K. and T.B. are employees and shareholders in Disarm Therapeutics. S.E.A. M.F. K.C. A.B. and P.S.K. are employees of Evotec SE. R.O.H. T.B. and A.B. are inventors on a patent related to isoquinoline inhibitors of SARM1 (WO 2019/236879 Al). The authors have no additional competing financial interests. Funding Information: We acknowledge use of the Australian Synchrotron MX facility and thank the staff for their support. We acknowledge the support and use of the Krios at the Midlands Regional Cryo-EM Facility, Institute of Structural and Chemical Biology, University of Leicester, UK. We also acknowledge the Centre for Microscopy and Microanalysis, University of Queensland and staff (Bill Close, Matthias Floetenmeyer, Richard Webb and Roger Wepf). The work was supported by the National Health and Medical Research Council (NHMRC grants 1196590 to T.V., 1107804 and 1160570 to B.K., and T.V., 1071659 to B.K., and 1108859 to T.V.), the Australian Research Council (ARC) Future Fellowship ( FT200100572 ) to T.V., the ARC Laureate Fellowship ( FL180100109 ) to B.K., the National Institutes of Health ( R01NS087632 to J.M. and A.D.) and Disarm Therapeutics . T.V. received ARC DECRA ( DE170100783 ) funding. Y.Shi was a recipient of Griffith University Postdoctoral Fellowship Scheme. F.K.S. was supported by the University of Queensland Research Training Scholarship . Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = may,
day = "5",
doi = "10.1016/j.molcel.2022.03.007",
language = "English",
volume = "82",
pages = "1643--1659.e10",
journal = "Molecular Cell",
issn = "1097-2765",
number = "9",
}