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- EMDB-74339: Human sterile alpha motif domain-containing protein 9 (SAMD9), monomer -

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Basic information

Entry
Database: EMDB / ID: EMD-74339
TitleHuman sterile alpha motif domain-containing protein 9 (SAMD9), monomer
Map data
Sample
  • Complex: SAMD9
    • Protein or peptide: Sterile alpha motif domain-containing protein 9
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: water
Keywordsinflammasome / signal transduction ATPases with numerous domains (STAND) / sterile alpha motif / poxvirus restriction factor / ANTIVIRAL PROTEIN
Function / homology
Function and homology information


endosomal vesicle fusion / innate immune response / cytosol / cytoplasm
Similarity search - Function
SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Sterile alpha motif domain-containing protein 9
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.53 Å
AuthorsMou Z / Zhang F / Dai X / Xiang Y
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI151638 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM151043 United States
CitationJournal: Sci Adv / Year: 2026
Title: Structural mechanisms of SAMD9 autoinhibition and pathogenic dysregulation.
Authors: Zongjun Mou / Fushun Zhang / Marisol Morales / Bibekananda Sahoo / Xinghong Dai / Yan Xiang /
Abstract: SAMD9 and SAMD9L (SAMD9/9L) are large cytosolic proteins essential for hematopoietic homeostasis and antiviral defense (-). Germline gain-of-function (GoF) mutations in SAMD9/9L cause severe ...SAMD9 and SAMD9L (SAMD9/9L) are large cytosolic proteins essential for hematopoietic homeostasis and antiviral defense (-). Germline gain-of-function (GoF) mutations in SAMD9/9L cause severe multisystem disorders and predispose to leukemia, but the mechanisms that regulate SAMD9/9L activity and how pathogenic mutations disrupt these processes remain poorly understood. Here, we report cryo-electron microscopy structures of human SAMD9 in multiple conformational and oligomeric states. SAMD9 predominantly adopts a closed, autoinhibited conformation stabilized by a central ATP-bound nucleotide-binding oligomerization domain (NOD) and an extensive network of intramolecular interactions. Recurrent patient-derived GoF mutations localize to and destabilize these intramolecular interfaces, whereas structure-guided compensatory mutations that restabilize these interfaces restore autoinhibition. We further identify low-abundance asymmetric SAMD9 dimers in which one protomer undergoes large conformational changes and establishes intermolecular interactions that are essential for SAMD9 activation. Together, these findings define the structural basis of SAMD9 autoinhibition and reveal how human GoF mutations disrupt this regulatory mechanism to drive disease.
History
DepositionDec 5, 2025-
Header (metadata) releaseFeb 25, 2026-
Map releaseFeb 25, 2026-
UpdateOct 7, 2026-
Current statusOct 7, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_74339.png

Downloads & links

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Map

FileDownload / File: emd_74339.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 512 pix.
= 337.92 Å		0.66 Å/pix.
x 512 pix.
= 337.92 Å		0.66 Å/pix.
x 512 pix.
= 337.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.66 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-2.9812648 - 4.677558
Average (Standard dev.)-0.00044939527 (±0.055457495)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 337.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_74339_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_74339_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 : SAMD9

EntireName: SAMD9
Components
  • Complex: SAMD9
    • Protein or peptide: Sterile alpha motif domain-containing protein 9
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: water

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Supramolecule #1: SAMD9

SupramoleculeName: SAMD9 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 168 kDa/nm

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Macromolecule #1: Sterile alpha motif domain-containing protein 9

MacromoleculeName: Sterile alpha motif domain-containing protein 9 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 168.699984 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDHDGDY KDHDIDSIDL TCVSYPFDEF SNPYRYKLDF SLQPETGPGN LIDPIHEFKA FTNTATATEE DVKMKFSNEV FRFASACMN SRTNGTIHFG VKDKPHGKIV GIKVTNDTKE ALINHFNLMI NKYFEDHQVQ QAKKCIREPR FVEVLLPNST L SDRFVIEV ...String:
MDYKDHDGDY KDHDIDSIDL TCVSYPFDEF SNPYRYKLDF SLQPETGPGN LIDPIHEFKA FTNTATATEE DVKMKFSNEV FRFASACMN SRTNGTIHFG VKDKPHGKIV GIKVTNDTKE ALINHFNLMI NKYFEDHQVQ QAKKCIREPR FVEVLLPNST L SDRFVIEV DIIPQFSECQ YDYFQIKMQN YNNKIWEQSK KFSLFVRDGT SSKDITKNKV DFRAFKADFK TLAESRKAAE EK FRAKTNK KEREGPKLVK LLTGNQDLLD NSYYEQYILV TNKCHPDQTK HLDFLKEIKW FAVLEFDPES NINGVVKAYK ESR VANLHF PSVYVEQKTT PNETISTLNL YHQPSWIFCN GRLDLDSEKY KPFDPSSWQR ERASDVRKLI SFLTHEDIMP RGKF LVVFL LLSSVDDPRD PLIETFCAFY QDLKGMENIL CICVHPHIFQ GWKDLLEARL IKHQDEISSQ CISALSLEEI NGTIL KLKS VTQSSKRLLP SIGLSTVLLK KEEDIMTALE IICENECEGT LLEKDKNKFL EFKASKEEDF YRGGKVSWWN FYFSSE SYS SPFVKRDKYE RLEAMIQNCA DSSKPTSTKI IHLYHHPGCG GTTLAMHILW ELRKKFRCAV LKNKTVDFSE IGEQVTS LI TYGAMNRQEY VPVLLLVDDF EEQDNVYLLQ YSIQTAIAKK YIRYEKPLVI ILNCMRSQNP EKSARIPDSI AVIQQLSP K EQRAFELKLK EIKEQHKNFE DFYSFMIMKT NFNKEYIENV VRNILKGQNI FTKEAKLFSF LALLNSYVPD TTISLSQCE KFLGIGNKKA FWGTEKFEDK MGTYSTILIK TEVIECGNYC GVRIIHSLIA EFSLEELKKS YHLNKSQIML DMLTENLFFD TGMGKSKFL QDMHTLLLTR HRDEHEGETG NWFSPFIEAL HKDEGNEAVE AVLLESIHRF NPNAFICQAL ARHFYIKKKD F GNALNWAK QAKIIEPDNS YISDTLGQVY KSKIRWWIEE NGGNGNISVD DLIALLDLAE HASSAFKESQ QQSEDREYEV KE RLYPKSK RRYDTYNIAG YQGEIEVGLY TIQILQLIPF FDNKNELSKR YMVNFVSGSS DIPGDPNNEY KLALKNYIPY LTK LKFSLK KSFDFFDEYF VLLKPRNNIK QNEEAKTRRK VAGYFKKYVD IFCLLEESQN NTGLGSKFSE PLQVERCRRN LVAL KADKF SGLLEYLIKS QEDAISTMKC IVNEYTFLLE QCTVKIQSKE KLNFILANII LSCIQPTSRL VKPVEKLKDQ LREVL QPIG LTYQFSEPYF LASLLFWPEN QQLDQHSEQM KEYAQALKNS FKGQYKHMHR TKQPIAYFFL GKGKRLERLV HKGKID QCF KKTPDINSLW QSGDVWKEEK VQELLLRLQG RAENNCLYIE YGINEKITIP ITPAFLGQLR SGRSIEKVSF YLGFSIG GP LAYDIEIV

UniProtKB: Sterile alpha motif domain-containing protein 9

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 1 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 178 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration1 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
50.0 mMTrisTris(hydroxymethyl)aminomethane hydrochloride
1.0 mMDTTDithiothreitol
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.53 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 388748
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC
FSC plot (resolution estimation)

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