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- EMDB-30700: Human SARM1 inhibitory state bounded with inhibitor dHNN -

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Basic information

Entry
Database: EMDB / ID: EMD-30700
TitleHuman SARM1 inhibitory state bounded with inhibitor dHNN
Map dataHuman SARM1 bounded with inhibitor dHNN
Sample
  • Cell: Human NAD(+) hydrolysis SARM1
    • Protein or peptide: NAD(+) hydrolase SARM1
  • Ligand: O3-methyl O5-(2-methylpropyl) 2,6-dimethyl-4-[2-(oxidanylamino)phenyl]pyridine-3,5-dicarboxylate
KeywordsNAD(+) hydrolase / HYDROLASE
Function / homology
Function and homology information


negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / NAD catabolic process / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / protein localization to mitochondrion / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / nervous system process ...negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / NAD catabolic process / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / protein localization to mitochondrion / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / 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 / nervous system development / microtubule / mitochondrial outer membrane / cell differentiation / axon / innate immune response / dendrite / synapse / signal transduction / 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: 2.8 Å
AuthorsCai Y / Zhang H
CitationJournal: Elife / Year: 2021
Title: Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate.
Authors: Wan Hua Li / Ke Huang / Yang Cai / Qian Wen Wang / Wen Jie Zhu / Yun Nan Hou / Sujing Wang / Sheng Cao / Zhi Ying Zhao / Xu Jie Xie / Yang Du / Chi-Sing Lee / Hon Cheung Lee / Hongmin Zhang / Yong Juan Zhao /
Abstract: SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative ...SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine (NSDP) as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.
History
DepositionNov 21, 2020-
Header (metadata) releaseMay 19, 2021-
Map releaseMay 19, 2021-
UpdateNov 15, 2023-
Current statusNov 15, 2023Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.143
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.143
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7djt
  • Surface level: 0.143
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7djt
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30700.png

Downloads & links

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Map

FileDownload / File: emd_30700.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman SARM1 bounded with inhibitor dHNN
Voxel sizeX=Y=Z: 1.076 Å
Density
Contour LevelBy AUTHOR: 0.143 / Movie #1: 0.143
Minimum - Maximum-0.4212005 - 0.85581076
Average (Standard dev.)0.0020005496 (±0.025466425)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 322.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0761.0761.076
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z322.800322.800322.800
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ512512512
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.4210.8560.002

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Supplemental data

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Sample components

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Entire : Human NAD(+) hydrolysis SARM1

EntireName: Human NAD(+) hydrolysis SARM1
Components
  • Cell: Human NAD(+) hydrolysis SARM1
    • Protein or peptide: NAD(+) hydrolase SARM1
  • Ligand: O3-methyl O5-(2-methylpropyl) 2,6-dimethyl-4-[2-(oxidanylamino)phenyl]pyridine-3,5-dicarboxylate

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Supramolecule #1: Human NAD(+) hydrolysis SARM1

SupramoleculeName: Human NAD(+) hydrolysis SARM1 / type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1
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: 76.659656 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: RLAVPGPDGG GGTGPWWAAG GRGPREVSPG AGTEVQDALE RALPELQQAL SALKQAGGAR AVGAGLAEVF QLVEEAWLLP AVGREVAQG LCDAIRLDGG LDLLLRLLQA PELETRVQAA RLLEQILVAE NRDRVARIGL GVILNLAKER EPVELARSVA G ILEHMFKH ...String:
RLAVPGPDGG GGTGPWWAAG GRGPREVSPG AGTEVQDALE RALPELQQAL SALKQAGGAR AVGAGLAEVF QLVEEAWLLP AVGREVAQG LCDAIRLDGG LDLLLRLLQA PELETRVQAA RLLEQILVAE NRDRVARIGL GVILNLAKER EPVELARSVA G ILEHMFKH SEETCQRLVA AGGLDAVLYW CRRTDPALLR HCALALGNCA LHGGQAVQRR MVEKRAAEWL FPLAFSKEDE LL RLHACLA VAVLATNKEV EREVERSGTL ALVEPLVASL DPGRFAR(VI3)LV DASDTSQGRG PDDLQRLVPL LDSNRLEAQ CIGAFYLCAE AAIKSLQGKT KVFSDIGAIQ SLKRLVSYST NGTKSALAKR ALRLLGEEVP RPILPSVPSW KEAEVQTWLQ QIGFSKYCE SFREQQVDGD LLLRLTEEEL QTDLGMKSGI TRKRFFRELT ELKTFANYST CDRSNLADWL GSLDPRFRQY T YGLVSCGL DRSLLHRVSE QQLLEDCGIH LGVHRARILT AAREMLHSPL PCTGGKPSGD TPDVFISYRR NSGSQLASLL KV HLQLHGF SVFIDVEKLE AGKFEDKLIQ SVMGARNFVL VLSPGALDKC MQDHDCKDWV HKEIVTALSC GKNIVPIIDG FEW PEPQVL PEDMQAVLTF NGIKWSHEYQ EATIEKIIRF LQGRSSRDSS AGSDTSLEGA APMGPT

UniProtKB: NAD(+) hydrolase SARM1

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Macromolecule #2: O3-methyl O5-(2-methylpropyl) 2,6-dimethyl-4-[2-(oxidanylamino)ph...

MacromoleculeName: O3-methyl O5-(2-methylpropyl) 2,6-dimethyl-4-[2-(oxidanylamino)phenyl]pyridine-3,5-dicarboxylate
type: ligand / ID: 2 / Number of copies: 8 / Formula: H8L
Molecular weightTheoretical: 372.415 Da
Chemical component information

ChemComp-H8L:
O3-methyl O5-(2-methylpropyl) 2,6-dimethyl-4-[2-(oxidanylamino)phenyl]pyridine-3,5-dicarboxylate

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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

Concentration3.00 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chloridesodium chloride
100.0 mMTrisTris
1.0 mMEDTAEthylenediaminetetraacetic acidEthylenediaminetetraacetic acid
VitrificationCryogen name: ETHANE / Details: BLOT TIME: 4S BLOT FORCE: -2.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated defocus max: -2.5 µm / Calibrated defocus min: -2.0 µm / Calibrated magnification: 130000 / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: -0.8 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Digitization - Frames/image: 4-36 / Number real images: 2673 / Average electron dose: 1.28 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2655835
Startup modelType of model: NONE
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: NOT APPLICABLE / Software - Name: cisTEM (ver. beta - 1.0.0)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cisTEM (ver. beta - 1.0.0) / Number images used: 247454

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-7djt:
Human SARM1 inhibitory state bounded with inhibitor dHNN

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