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. Landsberg; Aaron DiAntonio; Bostjan Kobe; Jeffrey Milbrandt; Robert O. Hughes; Thomas Ve

doi:10.1016/j.molcel.2022.03.007

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 journal › Article › peer-review

73 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 language	English
Pages (from-to)	1643-1659.e10
Journal	Molecular cell
Volume	82
Issue number	9
DOIs	https://doi.org/10.1016/j.molcel.2022.03.007
State	Published - May 5 2022

Keywords

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

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10.1016/j.molcel.2022.03.007

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Shi, Y., Kerry, P. S., Nanson, J. D., Bosanac, T., Sasaki, Y., Krauss, R., Saikot, F. K., Adams, S. E., Mosaiab, T., Masic, V., Mao, X., Rose, F., Vasquez, E., Furrer, M., Cunnea, K., Brearley, A., Gu, W., Luo, Z., Brillault, L., ... Ve, T. (2022). Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules. Molecular cell, 82(9), 1643-1659.e10. https://doi.org/10.1016/j.molcel.2022.03.007

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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 = "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",

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Shi, Y, Kerry, PS, Nanson, JD, Bosanac, T, Sasaki, Y, Krauss, R, Saikot, FK, Adams, SE, Mosaiab, T, Masic, V, Mao, X, Rose, F, Vasquez, E, Furrer, M, Cunnea, K, Brearley, A, Gu, W, Luo, Z, Brillault, L, Landsberg, MJ, DiAntonio, A, Kobe, B, Milbrandt, J, Hughes, RO & Ve, T 2022, 'Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules', Molecular cell, vol. 82, no. 9, pp. 1643-1659.e10. https://doi.org/10.1016/j.molcel.2022.03.007

TY - JOUR

T1 - Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules

AU - Shi, Yun

AU - Kerry, Philip S.

AU - Nanson, Jeffrey D.

AU - Bosanac, Todd

AU - Sasaki, Yo

AU - Krauss, Raul

AU - Saikot, Forhad K.

AU - Adams, Sarah E.

AU - Mosaiab, Tamim

AU - Masic, Veronika

AU - Mao, Xianrong

AU - Rose, Faith

AU - Vasquez, Eduardo

AU - Furrer, Marieke

AU - Cunnea, Katie

AU - Brearley, Andrew

AU - Gu, Weixi

AU - Luo, Zhenyao

AU - Brillault, Lou

AU - Landsberg, Michael J.

AU - DiAntonio, Aaron

AU - Kobe, Bostjan

AU - Milbrandt, Jeffrey

AU - Hughes, Robert O.

AU - Ve, Thomas

PY - 2022/5/5

Y1 - 2022/5/5

N2 - 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.

AB - 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.

KW - ARM domain

KW - NADase

KW - TIR domain

KW - X-ray crystallography

KW - allosteric activator

KW - base exchange

KW - cryo-EM

KW - orthosteric inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85129602813&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2022.03.007

DO - 10.1016/j.molcel.2022.03.007

M3 - Article

C2 - 35334231

AN - SCOPUS:85129602813

SN - 1097-2765

VL - 82

SP - 1643-1659.e10

JO - Molecular cell

JF - Molecular cell

IS - 9

ER -

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

Abstract

Keywords

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