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- EMDB-56479: SARM1 TIR with BEXi adduct 17 -

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Basic information

Entry
Database: EMDB / ID: EMD-56479
TitleSARM1 TIR with BEXi adduct 17
Map data
Sample
  • Complex: SARM1 TIR
    • Protein or peptide: NAD(+) hydrolase SARM1
  • Ligand: [[(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-[3-[(1~{S})-1-[4-[[2,2-bis(fluoranyl)-2-[(3~{R})-oxolan-3-yl]ethanoyl]amino]phenyl]ethyl]-2-methyl-imidazol-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate
KeywordsNad+ / Hydrolase / SARM1 / TIR
Function / homology
Function and homology information


negative regulation of MyD88-independent toll-like receptor signaling pathway / extrinsic component of synaptic membrane / MyD88-independent TLR4 cascade / NADP+ nucleosidase activity / Toll Like Receptor 3 (TLR3) Cascade / NAD+ nucleosidase activity / regulation of synapse pruning / modification of postsynaptic structure / NAD+ catabolic process / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase ...negative regulation of MyD88-independent toll-like receptor signaling pathway / extrinsic component of synaptic membrane / MyD88-independent TLR4 cascade / NADP+ nucleosidase activity / Toll Like Receptor 3 (TLR3) Cascade / NAD+ nucleosidase activity / regulation of synapse pruning / modification of postsynaptic structure / NAD+ catabolic process / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleosidase activity, cyclic ADP-ribose generating / protein localization to mitochondrion / nervous system process / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / regulation of dendrite morphogenesis / response to axon injury / response to glucose / signaling adaptor activity / regulation of neuron apoptotic process / 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 / cell differentiation / mitochondrial outer membrane / innate immune response / axon / 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: 2.94 Å
AuthorsSader K
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Other privateAstraZeneca United Kingdom
CitationJournal: Commun Chem / Year: 2026
Title: The rise and fall of SARM1 base-exchange inhibitors.
Authors: Thomas Lundbäck / Vijay Chandrasekar / Chendi Gu / Hyoungseok Ju / Robyn McAdam / Maria Palomero / Kasim Sader / Bradley Peter / Lisa Wissler / Philip Nevin / Edmund Foster / Tanguy Jamier ...Authors: Thomas Lundbäck / Vijay Chandrasekar / Chendi Gu / Hyoungseok Ju / Robyn McAdam / Maria Palomero / Kasim Sader / Bradley Peter / Lisa Wissler / Philip Nevin / Edmund Foster / Tanguy Jamier / Pravallika Manjappa / Carina Johansson / Jenny Sandmark / Mei Ding / Anette Persson-Kry / Sanhita Mitra / Tugce Munise Satir / Bilada Bilican / Mirko Messa / Graham Fraser / John Linley / Helen Plant / Rachel Moore / Tina Seifert / Michael Lerche / Carina Raynochek / Ewa Nilsson / Nour Majbour / Richard Lucey / Taiana Maia de Oliveira / Qi Wang / Iain Chessell / Perla Breccia / Rebecca Jarvis /
Abstract: The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral ...The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral neuropathy (CIPN) and other nervous system diseases. In this study, we identified and optimised a class of base-exchange inhibitors (BEXi) targeting human SARM1 and explored their molecular interactions and conformational effects using cryo-EM, HDX-MS and SAXS. Although BEXi produced robust inhibition across all biochemical and cellular assay formats, application at sub-inhibitory concentrations consistently led to paradoxical SARM1 activation, and in neuronal assays, accelerated neurite degeneration. Further analysis showed that BEXi only delayed, rather than prevented, neurite degeneration when applied to primary neuronal cells, even at exceedingly high inhibitor concentrations. These results prompted us to discontinue BEXi development in favour of alternative strategies, underscoring the complexity of SARM1 as a therapeutic target and the need for comprehensive, mechanistically informed screening cascades.
History
DepositionJan 25, 2026-
Header (metadata) releaseJun 3, 2026-
Map releaseJun 3, 2026-
UpdateJun 3, 2026-
Current statusJun 3, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_56479.png

Downloads & links

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Map

FileDownload / File: emd_56479.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.28 Å/pix.
x 180 pix.
= 230.4 Å		1.28 Å/pix.
x 180 pix.
= 230.4 Å		1.28 Å/pix.
x 180 pix.
= 230.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.28 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.217
Minimum - Maximum-1.1015272 - 1.6616083
Average (Standard dev.)0.0017646984 (±0.034987338)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 230.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_56479_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_56479_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : SARM1 TIR

EntireName: SARM1 TIR
Components
  • Complex: SARM1 TIR
    • Protein or peptide: NAD(+) hydrolase SARM1
  • Ligand: [[(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-[3-[(1~{S})-1-[4-[[2,2-bis(fluoranyl)-2-[(3~{R})-oxolan-3-yl]ethanoyl]amino]phenyl]ethyl]-2-methyl-imidazol-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate

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Supramolecule #1: SARM1 TIR

SupramoleculeName: SARM1 TIR / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: Assembly
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: 4 / Enantiomer: LEVO / EC number: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.148522 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
SDTPDVFISY RRNSGSQLAS LLKVHLQLHG FSVFIDVEKL EAGKFEDKLI QSVMGARNFV LVLSPGALDK CMQDHDCKDW VHKEIVTAL SCGKNIVPII DGFEWPEPQV LPEDMQAVLT FNGIKWSHEY QEATIEKIIR FLQ

UniProtKB: NAD(+) hydrolase SARM1

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Macromolecule #2: [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidany...

MacromoleculeName: [[(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-[3-[(1~{S})-1-[4-[[2,2-bis(fluoranyl)-2-[(3~{R})-oxolan- ...Name: [[(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-[3-[(1~{S})-1-[4-[[2,2-bis(fluoranyl)-2-[(3~{R})-oxolan-3-yl]ethanoyl]amino]phenyl]ethyl]-2-methyl-imidazol-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate
type: ligand / ID: 2 / Number of copies: 4 / Formula: A1JZ0
Molecular weightTheoretical: 891.683 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statefilament

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Sample preparation

Concentration4.3 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
10.0 mMC8H18N2O4SHEPES
150.0 mMNaClsodium chloride

Details: flash frozen and stored at -80C
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 2 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 10 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.00039000000000000005 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
Details: Calibrated blot force used to have blot pads just touching, blot time 6s..

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Electron microscopy

MicroscopeTFS KRIOS
TemperatureMin: 77.0 K / Max: 77.0 K
SoftwareName: EPU
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 18317 / Average exposure time: 4.68 sec. / Average electron dose: 60.0 e/Å2 / Details: Images were collected in EER mode.
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.4000000000000001 µm / Nominal magnification: 120000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 7667327
CTF correctionSoftware - Name: cryoSPARC (ver. 3.3.2) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

56477

Final reconstructionNumber classes used: 1 / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.2) / Number images used: 2643954
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.2) / Details: Ab initio refinement and particle separation.
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.2)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9tzw


Chain - Source name: PDB / Chain - Initial model type: experimental model
SoftwareName: Coot (ver. 0.9.8.92)
RefinementSpace: RECIPROCAL / Protocol: RIGID BODY FIT / Overall B value: 58
Output model

PDB-9tzy:
SARM1 TIR with BEXi adduct 17

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