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- EMDB-62773: Structure of SARM1 bound to M1 in the intermediate state 2 -

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Basic information

Entry
Database: EMDB / ID: EMD-62773
TitleStructure of SARM1 bound to M1 in the intermediate state 2
Map data
Sample
  • Complex: Structure of SARM1 bound to M1 in the intermediate state 2
    • Protein or peptide: NAD(+) hydrolase SARM1
KeywordsNAD(+) hydrolase / cell death / apoptosis / HYDROLASE
Function / homology
Function and homology information


extrinsic component of synaptic membrane / negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / NADP+ nucleosidase activity / Toll Like Receptor 3 (TLR3) Cascade / NAD+ catabolic process / NAD+ nucleosidase activity / regulation of synapse pruning / modification of postsynaptic structure / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase ...extrinsic component of synaptic membrane / negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / NADP+ nucleosidase activity / Toll Like Receptor 3 (TLR3) Cascade / NAD+ catabolic process / NAD+ nucleosidase activity / regulation of synapse pruning / modification of postsynaptic structure / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / protein localization to mitochondrion / NAD+ nucleosidase activity, cyclic ADP-ribose generating / nervous system process / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / regulation of dendrite morphogenesis / response to glucose / response to axon injury / regulation of neuron apoptotic process / signaling adaptor activity / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / IKK complex recruitment mediated by RIP1 / neuromuscular junction / nervous system development / microtubule / mitochondrial outer membrane / cell differentiation / axon / innate immune response / synapse / dendrite / glutamatergic synapse / cell surface / signal transduction / protein-containing complex / mitochondrion / identical protein binding / cytoplasm / cytosol
Similarity search - Function
Sterile alpha and TIR motif-containing protein 1 / TIR domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain ...Sterile alpha and TIR motif-containing protein 1 / TIR domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Armadillo-like helical / Armadillo-type fold
Similarity search - Domain/homology
NAD(+) hydrolase SARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.46 Å
AuthorsHuang Y / Zhang J / Zheng S / Wang X
Funding support China, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China) China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic.
Authors: Yinpin Huang / Jun Zhang / Wenbin Zhang / Jie Chen / Sijia Chen / Qincui Wu / Sanduo Zheng / Xiaodong Wang /
Abstract: Axon degeneration, driven by the NAD hydrolyzing enzyme SARM1, is an early pathological hallmark of numerous neurodegenerative diseases. SARM1 exists in an inactive form and is activated following ...Axon degeneration, driven by the NAD hydrolyzing enzyme SARM1, is an early pathological hallmark of numerous neurodegenerative diseases. SARM1 exists in an inactive form and is activated following nerve injury. However, the precise molecular mechanism underlying SARM1 activation remains to be fully elucidated. In this study, we report the identification of a potent proactivator of SARM1, G10, which is converted into a direct activator (M1) by the enzyme nicotinamide phosphoribosyltransferase. Cryoelectron microscopy structures of SARM1 bound to M1, as well as to M1 and a nonhydrolyzable NAD analog (1AD), captured two intermediate activation states and the fully active state, revealing a stepwise mechanism of SARM1 activation. Further, introducing a disulfide bond to prevent conformational transitions between the two intermediate states mediated by M1 stabilized SARM1 in its inactive form and blocked M1-induced cell death. Together, these findings propose a sequential, stepwise activation model for SARM1 and offer a framework for developing potential SARM1 inhibitors for the treatment of neurodegenerative diseases.
History
DepositionDec 17, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateSep 24, 2025-
Current statusSep 24, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62773.png

Downloads & links

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Map

FileDownload / File: emd_62773.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.81 Å/pix.
x 400 pix.
= 323.2 Å		0.81 Å/pix.
x 400 pix.
= 323.2 Å		0.81 Å/pix.
x 400 pix.
= 323.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.808 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.48
Minimum - Maximum-6.7126756 - 10.08755
Average (Standard dev.)-0.0016004456 (±0.16899912)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 323.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_62773_half_map_1.map
Projections & Slices
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Slices (1/2)
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Histogram

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Half map: #2

Fileemd_62773_half_map_2.map
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Sample components

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Entire : Structure of SARM1 bound to M1 in the intermediate state 2

EntireName: Structure of SARM1 bound to M1 in the intermediate state 2
Components
  • Complex: Structure of SARM1 bound to M1 in the intermediate state 2
    • Protein or peptide: NAD(+) hydrolase SARM1

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Supramolecule #1: Structure of SARM1 bound to M1 in the intermediate state 2

SupramoleculeName: Structure of SARM1 bound to M1 in the intermediate state 2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: NAD(+) hydrolase SARM1

MacromoleculeName: NAD(+) hydrolase SARM1 / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO / EC number: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 80.483133 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVLTLLLSAY KLCRFFAMSG PRPGAERLAV PGPDGGGGTG PWWAAGGRGP REVSPGAGTE VQDALERALP ELQQALSALK QAGGARAVG AGLAEVFQLV EEAWLLPAVG REVAQGLCDA IRLDGGLDLL LRLLQAPELE TRVQAARLLE QILVAENRDR V ARIGLGVI ...String:
MVLTLLLSAY KLCRFFAMSG PRPGAERLAV PGPDGGGGTG PWWAAGGRGP REVSPGAGTE VQDALERALP ELQQALSALK QAGGARAVG AGLAEVFQLV EEAWLLPAVG REVAQGLCDA IRLDGGLDLL LRLLQAPELE TRVQAARLLE QILVAENRDR V ARIGLGVI LNLAKEREPV ELARSVAGIL EHMFKHSEET CQRLVAAGGL DAVLYWCRRT DPALLRHCAL ALGNCALHGG QA VQRRMVE KRAAEWLFPL AFSKEDELLR LHACLAVAVL ATNKEVEREV ERSGTLALVE PLVASLDPGR FARCLVDASD TSQ GRGPDD LQRLVPLLDS NRLEAQCIGA FYLCAEAAIK SLQGKTKVFS DIGAIQSLKR LVSYSTNGTK SALAKRALRL LGEE VPRPI LPSVPSWKEA EVQTWLQQIG FSKYCESFRE QQVDGDLLLR LTEEELQTDL GMKSGITRKR FFRELTELKT FANYS TCDR SNLADWLGSL DPRFRQYTYG LVSCGLDRSL LHRVSEQQLL EDCGIHLGVH RARILTAARE MLHSPLPCTG GKPSGD TPD VFISYRRNSG SQLASLLKVH LQLHGFSVFI DVEKLEAGKF EDKLIQSVMG ARNFVLVLSP GALDKCMQDH DCKDWVH KE IVTALSCGKN IVPIIDGFEW PEPQVLPEDM QAVLTFNGIK WSHEYQEATI EKIIRFLQGR SSRDSSAGSD TSLEGAAP M GPTDYKDDDD K

UniProtKB: NAD(+) hydrolase SARM1

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 52.73 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.24 µm / Nominal defocus min: 0.71 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7cm5

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 244752
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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