[English] 日本語
Yorodumi
- EMDB-56477: SARM1 TIR with BEXi adduct 6 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-56477
TitleSARM1 TIR with BEXi adduct 6
Map data
Sample
  • Complex: SARM1
    • 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})-3,4-bis(oxidanyl)-5-[4-[[4-(pyridin-2-ylcarbamoylamino)phenyl]methyl]pyridin-1-yl]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: 3.3 Å
AuthorsSader KS / Oliveria TM
Funding support1 items
OrganizationGrant numberCountry
Other private
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 24, 2026-
Header (metadata) releaseJun 3, 2026-
Map releaseJun 3, 2026-
UpdateJun 3, 2026-
Current statusJun 3, 2026Processing site: PDBe / Status: Released

-
Structure visualization

Supplemental images

emd_56477.png

Downloads & links

-
Map

FileDownload / File: emd_56477.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.87 Å/pix.
x 400 pix.
= 349.973 Å		0.87 Å/pix.
x 400 pix.
= 349.973 Å		0.87 Å/pix.
x 400 pix.
= 349.973 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.87493 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.137
Minimum - Maximum-0.1590498 - 0.4599875
Average (Standard dev.)0.000057453384 (±0.012655388)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 349.9732 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Mask #1

Fileemd_56477_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #2

Fileemd_56477_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #1

Fileemd_56477_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : SARM1

EntireName: SARM1
Components
  • Complex: SARM1
    • 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})-3,4-bis(oxidanyl)-5-[4-[[4-(pyridin-2-ylcarbamoylamino)phenyl]methyl]pyridin-1-yl]oxolan-2-yl]methyl hydrogen phosphate

-
Supramolecule #1: SARM1

SupramoleculeName: SARM1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: TIR assembly
Source (natural)Organism: Homo sapiens (human)

-
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

-
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})-3,4-bis(oxidanyl)-5-[4-[[4-(pyridin-2-ylcarbamoylamino) ...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})-3,4-bis(oxidanyl)-5-[4-[[4-(pyridin-2-ylcarbamoylamino)phenyl]methyl]pyridin-1-yl]oxolan-2-yl]methyl hydrogen phosphate
type: ligand / ID: 2 / Number of copies: 4 / Formula: A1JZX
Molecular weightTheoretical: 846.654 Da

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

Concentration6.83 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
10.0 mMC8H18N2O4SHEPES
150.0 mMNaClsodium chloride
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 20 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.039 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: 2.5ul.
DetailsSample flash-frozen and stored at -80C.

-
Electron microscopy

MicroscopeTFS KRIOS
TemperatureMin: 77.0 K / Max: 77.0 K
Alignment procedureComa free - Residual tilt: 0.02 mrad
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: 3758 / Average exposure time: 4.38 sec. / Average electron dose: 43.0 e/Å2 / Details: Movies were collected in EER mode.
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated defocus max: 3.7 µm / Calibrated defocus min: 0.5 µm / Calibrated magnification: 213000 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 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

+
Image processing

Particle selectionNumber selected: 2535468
CTF correctionSoftware - Name: cryoSPARC (ver. 4.7.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab initio model generation in CryoSparc.
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Details: Non-uniform refinement / Number images used: 110926
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.7.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.7.1)
Final 3D classificationNumber classes: 3 / Avg.num./class: 80000 / Software - Name: cryoSPARC (ver. 4.7.1)
Details: Ab initio reconstruction with 3 classes with an window inner radius of 0.5, max resolution of 7A, min resolution of 12A, initial and final minibatch size of 8000 was used.
FSC plot (resolution estimation)

-
Atomic model buiding 1

Initial modelPDB ID:

7nak


Chain - Source name: PDB / Chain - Initial model type: experimental model
DetailsRigid body fitting of TIR monomers was done in Chimera, followed by realspace refinement in Coot, and finally refinement in Phenix.
RefinementSpace: RECIPROCAL / Protocol: RIGID BODY FIT / Overall B value: 62.3 / Target criteria: Cross-correlation
Output model

PDB-9tzw:
SARM1 TIR with BEXi adduct 6

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more