[English] 日本語
Yorodumi
- EMDB-13951: Inhibitor-induced hSARM1 duplex -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-13951
TitleInhibitor-induced hSARM1 duplex
Map datahSARM1 duplex
Sample
  • Complex: SARM1
    • Protein or peptide: NAD(+) hydrolase SARM1
KeywordsSARM1 / inhibitor / axon / degeneration / APOPTOSIS
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 / regulation of synapse pruning / modification of postsynaptic structure / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleosidase activity ...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 / regulation of synapse pruning / modification of postsynaptic structure / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleosidase activity / protein localization to mitochondrion / nervous system process / NAD+ nucleosidase activity, cyclic ADP-ribose generating / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / regulation of dendrite morphogenesis / response to axon injury / response to glucose / 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 / mitochondrial outer membrane / microtubule / cell differentiation / axon / innate immune response / dendrite / synapse / glutamatergic synapse / cell surface / signal transduction / protein-containing complex / mitochondrion / identical protein binding / cytosol / cytoplasm
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: 4.02 Å
AuthorsZalk R / Kahzma T
Funding support United States, 2 items
OrganizationGrant numberCountry
Israel Science Foundation909/19 United States
United States - Israel Binational Science Foundation (BSF)2019150 United States
CitationJournal: Cell Mol Life Sci / Year: 2022
Title: A duplex structure of SARM1 octamers stabilized by a new inhibitor.
Authors: Tami Khazma / Yarden Golan-Vaishenker / Julia Guez-Haddad / Atira Grossman / Radhika Sain / Michal Weitman / Alexander Plotnikov / Ran Zalk / Avraham Yaron / Michael Hons / Yarden Opatowsky /
Abstract: In recent years, there has been growing interest in SARM1 as a potential breakthrough drug target for treating various pathologies of axon degeneration. SARM1-mediated axon degeneration relies on its ...In recent years, there has been growing interest in SARM1 as a potential breakthrough drug target for treating various pathologies of axon degeneration. SARM1-mediated axon degeneration relies on its TIR domain NADase activity, but recent structural data suggest that the non-catalytic ARM domain could also serve as a pharmacological site as it has an allosteric inhibitory function. Here, we screened for synthetic small molecules that inhibit SARM1, and tested a selected set of these compounds in a DRG axon degeneration assay. Using cryo-EM, we found that one of the newly discovered inhibitors, a calmidazolium designated TK106, not only stabilizes the previously reported inhibited conformation of the octamer, but also a meta-stable structure: a duplex of octamers (16 protomers), which we have now determined to 4.0 Å resolution. In the duplex, each ARM domain protomer is engaged in lateral interactions with neighboring protomers, and is further stabilized by contralateral contacts with the opposing octamer ring. Mutagenesis of the duplex contact sites leads to a moderate increase in SARM1 activation in cultured cells. Based on our data we propose that the duplex assembly constitutes an additional auto-inhibition mechanism that tightly prevents pre-mature activation and axon degeneration.
History
DepositionDec 7, 2021-
Header (metadata) releaseDec 21, 2022-
Map releaseDec 21, 2022-
UpdateJul 17, 2024-
Current statusJul 17, 2024Processing site: PDBe / Status: Released

-
Structure visualization

Supplemental images

emd_13951.png

Downloads & links

-
Map

FileDownload / File: emd_13951.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationhSARM1 duplex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 400 pix.
= 335.6 Å		0.84 Å/pix.
x 400 pix.
= 335.6 Å		0.84 Å/pix.
x 400 pix.
= 335.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.839 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.13
Minimum - Maximum-0.36071873 - 0.74931675
Average (Standard dev.)0.002008079 (±0.035107378)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 335.6 Å
α=β=γ: 90.0 °

-
Supplemental data

-
Sample components

-
Entire : SARM1

EntireName: SARM1
Components
  • Complex: SARM1
    • Protein or peptide: NAD(+) hydrolase SARM1

-
Supramolecule #1: SARM1

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

-
Macromolecule #1: NAD(+) hydrolase SARM1

MacromoleculeName: NAD(+) hydrolase SARM1 / type: protein_or_peptide / ID: 1 / Number of copies: 16 / Enantiomer: LEVO / EC number: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 79.971258 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSYHHHHHHD YDIPTTENLY FQGAMGSERL AVPGPDGGGG TGPWWAAGGR GPREVSPGAG TEVQDALERA LPELQQALSA LKQAGGARA VGAGLAEVFQ LVEEAWLLPA VGREVAQGLC DAIRLDGGLD LLLRLLQAPE LETRVQAARL LEQILVAENR D RVARIGLG ...String:
MSYHHHHHHD YDIPTTENLY FQGAMGSERL AVPGPDGGGG TGPWWAAGGR GPREVSPGAG TEVQDALERA LPELQQALSA LKQAGGARA VGAGLAEVFQ LVEEAWLLPA VGREVAQGLC DAIRLDGGLD LLLRLLQAPE LETRVQAARL LEQILVAENR D RVARIGLG VILNLAKERE PVELARSVAG ILEHMFKHSE ETCQRLVAAG GLDAVLYWCR RTDPALLRHC ALALGNCALH GG QAVQRRM VEKRAAEWLF PLAFSKEDEL LRLHACLAVA VLATNKEVER EVERSGTLAL VEPLVASLDP GRFARCLVDA SDT SQGRGP DDLQRLVPLL DSNRLEAQCI GAFYLCAEAA IKSLQGKTKV FSDIGAIQSL KRLVSYSTNG TKSALAKRAL RLLG EEVPR PILPSVPSWK EAEVQTWLQQ IGFSKYCESF REQQVDGDLL LRLTEEELQT DLGMKSGITR KRFFRELTEL KTFAN YSTC DRSNLADWLG SLDPRFRQYT YGLVSCGLDR SLLHRVSEQQ LLEDCGIHLG VHRARILTAA REMLHSPLPC TGGKPS GDT PDVFISYRRN SGSQLASLLK VHLQLHGFSV FIDVEKLEAG KFEDKLIQSV MGARNFVLVL SPGALDKCMQ DHDCKDW VH KQIVTALSCG KNIVPIIDGF EWPEPQVLPE DMQAVLTFNG IKWSHEYQEA TIEKIIRFLQ GRSSRDSSAG SDTSLEGA A PMGPT

UniProtKB: NAD(+) hydrolase SARM1

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
Sample preparation

BufferpH: 8.5
VitrificationCryogen name: ETHANE

-
Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

-
Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7anw

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.02 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 28303
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

+
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