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- PDB-9tzy: SARM1 TIR with BEXi adduct 17 -

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Basic information

Entry
Database: PDB / ID: 9tzy
TitleSARM1 TIR with BEXi adduct 17
ComponentsNAD(+) hydrolase SARM1
KeywordsHYDROLASE / Nad+ / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.94 Å
AuthorsSader, K.
Funding support United Kingdom, 1items
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, 2026Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 3, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NAD(+) hydrolase SARM1
C: NAD(+) hydrolase SARM1
D: NAD(+) hydrolase SARM1
B: NAD(+) hydrolase SARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,1618
Polymers64,5944
Non-polymers3,5674
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
NAD(+) hydrolase SARM1 / NADase SARM1 / hSARM1 / NADP(+) hydrolase SARM1 / Sterile alpha and Armadillo repeat protein / ...NADase SARM1 / hSARM1 / NADP(+) hydrolase SARM1 / Sterile alpha and Armadillo repeat protein / Sterile alpha and TIR motif-containing protein 1 / Sterile alpha motif domain-containing protein 2 / MyD88-5 / SAM domain-containing protein 2 / Tir-1 homolog / HsTIR


Mass: 16148.522 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SARM1, KIAA0524, SAMD2, SARM / Production host: Escherichia coli (E. coli)
References: UniProt: Q6SZW1, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase, Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds
#2: Chemical
ChemComp-A1JZ0 / [[(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


Mass: 891.683 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H43F2N8O15P2
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: SARM1 TIR / Type: COMPLEX / Details: Assembly / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5 / Details: flash frozen and stored at -80C
Buffer component
IDConc.NameFormulaBuffer-ID
110 mMHEPESC8H18N2O4S1
2150 mMsodium chlorideNaCl1
SpecimenConc.: 4.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K
Details: Calibrated blot force used to have blot pads just touching, blot time 6s.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 120000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 1400 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: ZEMLIN TABLEAU
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 77 K / Temperature (min): 77 K
Image recordingAverage exposure time: 4.68 sec. / Electron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 18317 / Details: Images were collected in EER mode.
Image scansSampling size: 14 µm / Width: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategory
1cryoSPARC3.3.2particle selection
2EPUimage acquisition
4cryoSPARC3.3.2CTF correction
7Coot0.9.8.92model fitting
9cryoSPARC3.3.2initial Euler assignment
10cryoSPARC3.3.2final Euler assignment
12cryoSPARC3.3.23D reconstruction
13PHENIX1.21.1_5286model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 7667327
3D reconstructionResolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2643954 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingB value: 58 / Protocol: RIGID BODY FIT / Space: RECIPROCAL
Atomic model buildingPDB-ID: 9TZW

9tzw


Accession code: 9TZW / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.94 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)

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