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Structure paper

TitleStructural basis of SARM1 activation, substrate recognition, and inhibition by small molecules.
Journal, issue, pagesMol Cell, Vol. 82, Issue 9, Page 1643-1659.e10, Year 2022
Publish dateMay 5, 2022
AuthorsYun 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 /
PubMed AbstractThe 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 ...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.
External linksMol Cell / PubMed:35334231 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.6 - 8.5 Å
Structure data

24272

7nak

EMDB-24272, PDB-7nak:
Cryo-EM structure of activated human SARM1 in complex with NMN and 1AD (TIR:1AD)
Method: EM (single particle) / Resolution: 2.9 Å

24273

7nal

EMDB-24273, PDB-7nal:
Cryo-EM structure of activated human SARM1 in complex with NMN and 1AD (ARM and SAM domains)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-24274: Cryo-EM structure of activated human SARM1 in complex with NMN and 1AD (SAM-TIR:1AD)
Method: EM (single particle) / Resolution: 4.6 Å

EMDB-26191: Cryo-EM structure of human SARM1 TIR domain in complex with 1AD
Method: EM (single particle) / Resolution: 8.5 Å

PDB-7nag:
Crystal structure of the TIR domain from human SARM1 in complex with 1AD
Method: X-RAY DIFFRACTION / Resolution: 1.72 Å

PDB-7nah:
Crystal structure of the TIR domain from human SARM1 in complex with 2AD
Method: X-RAY DIFFRACTION / Resolution: 1.79 Å

PDB-7nai:
Crystal structure of the TIR domain from human SARM1 in complex with 3AD
Method: X-RAY DIFFRACTION / Resolution: 1.74 Å

PDB-7naj:
Crystal structure of the TIR domain from human SARM1 in complex with ara-2'F-ADPR
Method: X-RAY DIFFRACTION / Resolution: 1.6 Å

Chemicals

ChemComp-1QD:
[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-5-(5-iodanylisoquinolin-2-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate

ChemComp-HOH:
WATER / Water

ChemComp-1OF:
[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-3,4-bis(oxidanyl)-5-(8-oxidanylidene-7~{H}-2,7-naphthyridin-2-yl)oxolan-2-yl]methyl hydrogen phosphate

ChemComp-1O4:
[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-5-(8-azanylisoquinolin-2-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate

ChemComp-1LK:
1,4-anhydro-2-deoxy-2-fluoro-5-O-[(S)-hydroxy(phosphonooxy)phosphoryl]-D-arabinitol

ChemComp-NMN:
BETA-NICOTINAMIDE RIBOSE MONOPHOSPHATE / Nicotinamide mononucleotide

Source
  • homo sapiens (human)
KeywordsHYDROLASE / NADase / Axon degeneration / HYDROLASE/Inhibitor / inhibitor / HYDROLASE-Inhibitor complex / complex

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