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- EMDB-18734: Cryo-EM structure of tetrameric human SAMHD1 State V - Depleted r... -

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Basic information

Entry
Database: EMDB / ID: EMD-18734
TitleCryo-EM structure of tetrameric human SAMHD1 State V - Depleted relaxed
Map data
Sample
  • Complex: homotetramer of SAMHD1
    • Protein or peptide: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
  • Ligand: GUANOSINE-5'-TRIPHOSPHATEGuanosine triphosphate
  • Ligand: FE (III) ION
  • Ligand: MAGNESIUM ION
  • Ligand: 2'-DEOXYADENOSINE 5'-TRIPHOSPHATE
  • Ligand: 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE
KeywordsTRIPHOSPHOHYDROLASE / METALLO-ENZYME / BINUCLEAR / HD / HYDROLASE
Function / homology
Function and homology information


Nucleotide catabolism / Hydrolases; Acting on ester bonds; Triphosphoric-monoester hydrolases / deoxynucleoside triphosphate hydrolase activity / triphosphoric monoester hydrolase activity / dGTP binding / dATP catabolic process / dGTPase activity / tetraspanin-enriched microdomain / DNA strand resection involved in replication fork processing / deoxyribonucleotide catabolic process ...Nucleotide catabolism / Hydrolases; Acting on ester bonds; Triphosphoric-monoester hydrolases / deoxynucleoside triphosphate hydrolase activity / triphosphoric monoester hydrolase activity / dGTP binding / dATP catabolic process / dGTPase activity / tetraspanin-enriched microdomain / DNA strand resection involved in replication fork processing / deoxyribonucleotide catabolic process / dGTP catabolic process / negative regulation of type I interferon-mediated signaling pathway / regulation of innate immune response / somatic hypermutation of immunoglobulin genes / RNA nuclease activity / double-strand break repair via homologous recombination / Interferon alpha/beta signaling / site of double-strand break / single-stranded DNA binding / protein homotetramerization / defense response to virus / nucleic acid binding / immune response / innate immune response / DNA damage response / GTP binding / RNA binding / zinc ion binding / nucleoplasm / identical protein binding / nucleus / plasma membrane
Similarity search - Function
HD domain profile. / HD domain / HD domain / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Metal dependent phosphohydrolases with conserved 'HD' motif. / Sterile alpha motif domain / HD/PDEase domain / Sterile alpha motif/pointed domain superfamily
Similarity search - Domain/homology
Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.43 Å
AuthorsActon OJ / Sheppard D / Rosenthal PB / Taylor IA
Funding support United Kingdom, 3 items
OrganizationGrant numberCountry
Cancer Research UKCC2029.CC2106 United Kingdom
Medical Research Council (MRC, United Kingdom)CC2029.CC2106 United Kingdom
Wellcome TrustCC2029.CC2106 United Kingdom
CitationJournal: Nat Commun / Year: 2024
Title: Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis.
Authors: Oliver J Acton / Devon Sheppard / Simone Kunzelmann / Sarah J Caswell / Andrea Nans / Ailidh J O Burgess / Geoff Kelly / Elizabeth R Morris / Peter B Rosenthal / Ian A Taylor /
Abstract: SAMHD1 regulates cellular nucleotide homeostasis, controlling dNTP levels by catalysing their hydrolysis into 2'-deoxynucleosides and triphosphate. In differentiated CD4+ macrophage and resting T- ...SAMHD1 regulates cellular nucleotide homeostasis, controlling dNTP levels by catalysing their hydrolysis into 2'-deoxynucleosides and triphosphate. In differentiated CD4+ macrophage and resting T-cells SAMHD1 activity results in the inhibition of HIV-1 infection through a dNTP blockade. In cancer, SAMHD1 desensitizes cells to nucleoside-analogue chemotherapies. Here we employ time-resolved cryogenic-EM imaging and single-particle analysis to visualise assembly, allostery and catalysis by this multi-subunit enzyme. Our observations reveal how dynamic conformational changes in the SAMHD1 quaternary structure drive the catalytic cycle. We capture five states at high-resolution in a live catalytic reaction, revealing how allosteric activators support assembly of a stable SAMHD1 tetrameric core and how catalysis is driven by the opening and closing of active sites through pairwise coupling of active sites and order-disorder transitions in regulatory domains. This direct visualisation of enzyme catalysis dynamics within an allostery-stabilised platform sets a precedent for mechanistic studies into the regulation of multi-subunit enzymes.
History
DepositionOct 24, 2023-
Header (metadata) releaseMay 15, 2024-
Map releaseMay 15, 2024-
UpdateMay 22, 2024-
Current statusMay 22, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18734.png

Downloads & links

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Map

FileDownload / File: emd_18734.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.09 Å
Density
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-4.2980247 - 7.5740304
Average (Standard dev.)0.0056795394 (±0.13935399)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 327.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_18734_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_18734_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : homotetramer of SAMHD1

EntireName: homotetramer of SAMHD1
Components
  • Complex: homotetramer of SAMHD1
    • Protein or peptide: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
  • Ligand: GUANOSINE-5'-TRIPHOSPHATEGuanosine triphosphate
  • Ligand: FE (III) ION
  • Ligand: MAGNESIUM ION
  • Ligand: 2'-DEOXYADENOSINE 5'-TRIPHOSPHATE
  • Ligand: 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE

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Supramolecule #1: homotetramer of SAMHD1

SupramoleculeName: homotetramer of SAMHD1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1

MacromoleculeName: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 72.305414 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MQRADSEQPS KRPRCDDSPR TPSNTPSAEA DWSPGLELHP DYKTWGPEQV CSFLRRGGFE EPVLLKNIRE NEITGALLPC LDESRFENL GVSSLGERKK LLSYIQRLVQ IHVDTMKVIN DPIHGHIELH PLLVRIIDTP QFQRLRYIKQ LGGGYYVFPG A SHNRFEHS ...String:
MQRADSEQPS KRPRCDDSPR TPSNTPSAEA DWSPGLELHP DYKTWGPEQV CSFLRRGGFE EPVLLKNIRE NEITGALLPC LDESRFENL GVSSLGERKK LLSYIQRLVQ IHVDTMKVIN DPIHGHIELH PLLVRIIDTP QFQRLRYIKQ LGGGYYVFPG A SHNRFEHS LGVGYLAGCL VHALGEKQPE LQISERDVLC VQIAGLCHDL GHGPFSHMFD GRFIPLARPE VKWTHEQGSV MM FEHLINS NGIKPVMEQY GLIPEEDICF IKEQIVGPLE SPVEDSLWPY KGRPENKSFL YEIVSNKRNG IDVDKWDYFA RDC HHLGIQ NNFDYKRFIK FARVCEVDNE LRICARDKEV GNLYDMFHTR NSLHRRAYQH KVGNIIDTMI TDAFLKADDY IEIT GAGGK KYRISTAIDD MEAYTKLTDN IFLEILYSTD PKLKDAREIL KQIEYRNLFK YVGETQPTGQ IKIKREDYES LPKEV ASAK PKVLLDVKLK AEDFIVDVIN MDYGMQEKNP IDHVSFYCKT APNRAIRITK NQVSQLLPEK FAEQLIRVYC KKVDRK SLY AARQYFVQWC ADRNFTKPQD GDVIAPLITP QKKEWNDSTS VQNPTRLREA SKSRVQLFKD DPM

UniProtKB: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1

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Macromolecule #2: GUANOSINE-5'-TRIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 4 / Formula: GTP
Molecular weightTheoretical: 523.18 Da
Chemical component information

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM / Guanosine triphosphate

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Macromolecule #3: FE (III) ION

MacromoleculeName: FE (III) ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: FE
Molecular weightTheoretical: 55.845 Da

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: 2'-DEOXYADENOSINE 5'-TRIPHOSPHATE

MacromoleculeName: 2'-DEOXYADENOSINE 5'-TRIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 2 / Formula: DTP
Molecular weightTheoretical: 491.182 Da
Chemical component information

ChemComp-DTP:
2'-DEOXYADENOSINE 5'-TRIPHOSPHATE / Deoxyadenosine triphosphate

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Macromolecule #6: 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE

MacromoleculeName: 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE / type: ligand / ID: 6 / Number of copies: 2 / Formula: DCP
Molecular weightTheoretical: 467.157 Da
Chemical component information

ChemComp-DCP:
2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE / Deoxycytidine triphosphate

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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

BufferpH: 7.8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: LAB6
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 75000
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 33.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.43 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 26844
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8qxo:
Cryo-EM structure of tetrameric human SAMHD1 State V - Depleted relaxed

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