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Yorodumi- EMDB-24274: Cryo-EM structure of activated human SARM1 in complex with NMN an... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-24274 | |||||||||
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Title | Cryo-EM structure of activated human SARM1 in complex with NMN and 1AD (SAM-TIR:1AD) | |||||||||
Map data | Half map A | |||||||||
Sample |
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Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.6 Å | |||||||||
Authors | Kerry PS / Adams S / Cunnea K / Brearley A / Bosanac T / Hughes RO / Ve T | |||||||||
Funding support | Australia, 2 items
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Citation | Journal: Mol Cell / Year: 2022 Title: Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules. Authors: Yun Shi / Philip S Kerry / Jeffrey D Nanson / Todd Bosanac / Yo Sasaki / Raul Krauss / Forhad K Saikot / Sarah E Adams / Tamim Mosaiab / Veronika Masic / Xianrong Mao / Faith Rose / Eduardo ...Authors: Yun Shi / Philip S Kerry / Jeffrey D Nanson / Todd Bosanac / Yo Sasaki / Raul Krauss / Forhad K Saikot / Sarah E Adams / Tamim Mosaiab / Veronika Masic / Xianrong Mao / Faith Rose / Eduardo Vasquez / Marieke Furrer / Katie Cunnea / Andrew Brearley / Weixi Gu / Zhenyao Luo / Lou Brillault / Michael J Landsberg / Aaron DiAntonio / Bostjan Kobe / Jeffrey Milbrandt / Robert O Hughes / Thomas Ve / Abstract: The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 ...The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD mimetics and the allosteric activator nicotinamide mononucleotide (NMN). NMN binding triggers reorientation of the armadillo repeat (ARM) domains, which disrupts ARM:TIR interactions and leads to formation of a two-stranded TIR domain assembly. The active site spans two molecules in these assemblies, explaining the requirement of TIR domain self-association for NADase activity and axon degeneration. Our results reveal the mechanisms of SARM1 activation and substrate binding, providing rational avenues for the design of new therapeutics targeting SARM1. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_24274.map.gz | 97.2 MB | EMDB map data format | |
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Header (meta data) | emd-24274-v30.xml emd-24274.xml | 16.2 KB 16.2 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_24274_fsc.xml | 10.4 KB | Display | FSC data file |
Images | emd_24274.png | 63.1 KB | ||
Masks | emd_24274_msk_1.map | 103 MB | Mask map | |
Others | emd_24274_half_map_1.map.gz emd_24274_half_map_2.map.gz | 95.7 MB 95.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-24274 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-24274 | HTTPS FTP |
-Validation report
Summary document | emd_24274_validation.pdf.gz | 749.4 KB | Display | EMDB validaton report |
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Full document | emd_24274_full_validation.pdf.gz | 749 KB | Display | |
Data in XML | emd_24274_validation.xml.gz | 18.2 KB | Display | |
Data in CIF | emd_24274_validation.cif.gz | 23.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-24274 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-24274 | HTTPS FTP |
-Related structure data
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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-Map
File | Download / File: emd_24274.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Half map A | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.086 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_24274_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: Sharpened map
File | emd_24274_half_map_1.map | ||||||||||||
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Annotation | Sharpened map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map B
File | emd_24274_half_map_2.map | ||||||||||||
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Annotation | Half map B | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : human SARM1 in complex with NMN and 1AD
Entire | Name: human SARM1 in complex with NMN and 1AD |
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Components |
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-Supramolecule #1: human SARM1 in complex with NMN and 1AD
Supramolecule | Name: human SARM1 in complex with NMN and 1AD / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Macromolecule #1: human SARM1
Macromolecule | Name: human SARM1 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: LAVPGPDGGG GTGPWWAAGG RGPREVSPGA GTEVQDALER ALPELQQALS ALKQAGGARA VGAGLAEVFQ LVEEAWLLPA VGREVAQGL CDAIRLDGGL DLLLRLLQAP ELETRVQAAR LLEQILVAEN RDRVARIGLG VILNLAKERE PVELARSVAG I LEHMFKHS ...String: LAVPGPDGGG GTGPWWAAGG RGPREVSPGA GTEVQDALER ALPELQQALS ALKQAGGARA VGAGLAEVFQ LVEEAWLLPA VGREVAQGL CDAIRLDGGL DLLLRLLQAP ELETRVQAAR LLEQILVAEN RDRVARIGLG VILNLAKERE PVELARSVAG I LEHMFKHS EETCQRLVAA GGLDAVLYWC RRTDPALLRH CALALGNCAL HGGQAVQRRM VEKRAAEWLF PLAFSKEDEL LR LHACLAV AVLATNKEVE REVERSGTLA LVEPLVASLD PGRFARCLVD ASDTSQGRGP DDLQRLVPLL DSNRLEAQCI GAF YLCAEA AIKSLQGKTK VFSDIGAIQS LKRLVSYSTN GTKSALAKRA LRLLGEEVPR PILPSVPSWK EAEVQTWLQQ IGFS KYCES FREQQVDGDL LLRLTEEELQ TDLGMKSGIT RKRFFRELTE LKTFANYSTC DRSNLADWLG SLDPRFRQYT YGLVS CGLD RSLLHRVSEQ QLLEDCGIHL GVHRARILTA AREMLHSPLP CTGGKPSGDT PDVFISYRRN SGSQLASLLK VHLQLH GFS VFIDVEKLEA GKFEDKLIQS VMGARNFVLV LSPGALDKCM QDHDCKDWVH KEIVTALSCG KNIVPIIDGF EWPEPQV LP EDMQAVLTFN GIKWSHEYQE ATIEKIIRFL QGRSSRDSSA GSDTSLEGAA PMGPT |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.6 mg/mL |
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Buffer | pH: 7.5 |
Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | TFS KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.9 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: OTHER / Imaging mode: OTHER / Cs: 2.7 mm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |