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- EMDB-26191: Cryo-EM structure of human SARM1 TIR domain in complex with 1AD -

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Basic information

Entry
Database: EMDB / ID: EMD-26191
TitleCryo-EM structure of human SARM1 TIR domain in complex with 1AD
Map dataMain map of hSARM1-TIR : 1AD complex
Sample
  • Complex: Active state assembly of hSARM1-TIR domain with 1AD.
    • Other: hSARM1-TIR domain : 1AD complex
KeywordsNADase / Axon degeneration / Inhibitor / Complex / CYTOSOLIC PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 8.5 Å
AuthorsSaikot FK / Kobe B / Ve T / Nanson JD / Gu W / Luo Z / Brillault L / Landsberg MJ
Funding support Australia, 1 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia) Australia
CitationJournal: Mol Cell / Year: 2022
Title: Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules.
Authors: 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 ...Authors: 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 /
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 ...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.
History
DepositionFeb 14, 2022-
Header (metadata) releaseMay 11, 2022-
Map releaseMay 11, 2022-
UpdateJan 17, 2024-
Current statusJan 17, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26191.png

Downloads & links

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Map

FileDownload / File: emd_26191.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMain map of hSARM1-TIR : 1AD complex
Voxel sizeX=Y=Z: 0.96 Å
Density
Contour LevelBy AUTHOR: 0.048
Minimum - Maximum-0.1385576 - 0.32481557
Average (Standard dev.)0.000043250526 (±0.010944257)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions450450450
Spacing450450450
CellA=B=C: 432.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_26191_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Sharpened map of hSARM1-TIR : 1AD complex

Fileemd_26191_additional_1.map
AnnotationSharpened map of hSARM1-TIR : 1AD complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half A volume map of hSARM1-TIR : 1AD complex

Fileemd_26191_half_map_1.map
AnnotationHalf A volume map of hSARM1-TIR : 1AD complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half B volume map of hSARM1-TIR : 1AD complex

Fileemd_26191_half_map_2.map
AnnotationHalf B volume map of hSARM1-TIR : 1AD complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Active state assembly of hSARM1-TIR domain with 1AD.

EntireName: Active state assembly of hSARM1-TIR domain with 1AD.
Components
  • Complex: Active state assembly of hSARM1-TIR domain with 1AD.
    • Other: hSARM1-TIR domain : 1AD complex

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Supramolecule #1: Active state assembly of hSARM1-TIR domain with 1AD.

SupramoleculeName: Active state assembly of hSARM1-TIR domain with 1AD. / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: hSARM1-TIR domain : 1AD complex

MacromoleculeName: hSARM1-TIR domain : 1AD complex / type: other / ID: 1
Details: 1AD = Base exchanged product of NAD+ and 5-iodoisoquinoline
Classification: other
Source (natural)Organism: Homo sapiens (human)
SequenceString:
SNATPDVFIS YRRNSGSQLA SLLKVHLQLH GFSVFIDVEK LEAGKFEDKL IQSVMGARNF VLVLSPGALD KCMQDHDCKD WVHKEIVTAL SCGKNIVPII DGFEWPEPQV LPEDMQAVLT FNGIKWSHEY QEATIEKIIR FLQ
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration3 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R2/2 / Material: GOLD / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample was oligomer.

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Electron microscopy

MicroscopeJEOL CRYO ARM 300
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 50000
Specialist opticsEnergy filter - Name: In-column Omega Filter / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: JEOL CRYOSPECPORTER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 247 / Average exposure time: 5.0 sec. / Average electron dose: 65.1 e/Å2

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Image processing

Particle selectionNumber selected: 25502
Startup modelType of model: OTHER / Details: Ab initio
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 2 / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final reconstructionNumber classes used: 2 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 8.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 5011
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT

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