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- PDB-9n2r: Structure of GTP-bound GM4951 -

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Basic information

Entry
Database: PDB / ID: 9n2r
TitleStructure of GTP-bound GM4951
ComponentsInterferon inducible GTPase 1C
KeywordsLIPID BINDING PROTEIN / Lipid droplet associated protein / GTPase
Function / homology
Function and homology information


autophagosome assembly / cellular response to interferon-beta / innate immune response / GTPase activity / endoplasmic reticulum membrane / GTP binding
Similarity search - Function
Immunity-related GTPases-like / : / Interferon-inducible GTPase (IIGP) / IRG-type guanine nucleotide-binding (G) domain / IRG-type guanine nucleotide-binding (G) domain profile. / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE / Interferon inducible GTPase 1C
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsRaj, R. / Beutler, B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI125581 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into GM4951 as a lipid droplet GTPase regulating hepatic lipid metabolism.
Authors: Rishi Raj / Yiao Jiang / Rahul Kumar Jha / Eva Marie Y Moresco / Himanshu Joshi / Zhao Zhang / Bruce Beutler /
Abstract: GM4951 is an immunity-related GTPase (IRG) that counteracts hepatic lipid accumulation in mice fed a high-fat diet. We determine full-length protein structures of GTPγS- and GDP-bound GM4951, and ...GM4951 is an immunity-related GTPase (IRG) that counteracts hepatic lipid accumulation in mice fed a high-fat diet. We determine full-length protein structures of GTPγS- and GDP-bound GM4951, and two missense mutants (N86K or D125G) associated with metabolic dysfunction-associated steatotic liver disease (MASLD) in mice. All four structures reveal a conserved GTPase domain fold and a helix bundle composed of the N- and C-terminal regions. Each mutation alters the dynamics of the switch-I and switch-II loops important for catalytic function and lipid droplet (LD) localization. GM4951 predominantly forms dimers in vitro. Cryo-electron microscopy reveals a dimer interface formed by the helical domains of two protomers (tail to tail), distinct from other IRGs. The N-terminal helices are necessary for LD localization, while a disulfide bond between helices in the GTPase domain and C-terminus is necessary for interaction with MASLD-associated HSD17B13. Distinct N- and C-terminal conformations set GM4951 apart from other IRGs structurally and functionally.
History
DepositionJan 29, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 14, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Interferon inducible GTPase 1C
A: Interferon inducible GTPase 1C
C: Interferon inducible GTPase 1C
D: Interferon inducible GTPase 1C
E: Interferon inducible GTPase 1C
F: Interferon inducible GTPase 1C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)296,22331
Polymers291,3736
Non-polymers4,85025
Water70339
1
F: Interferon inducible GTPase 1C
hetero molecules

B: Interferon inducible GTPase 1C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,6639
Polymers97,1242
Non-polymers1,5397
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_455x-1,y,z1
Buried area5390 Å2
ΔGint-27 kcal/mol
Surface area37510 Å2
MethodPISA
2
A: Interferon inducible GTPase 1C
hetero molecules

E: Interferon inducible GTPase 1C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,5718
Polymers97,1242
Non-polymers1,4476
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_565x,y+1,z1
Buried area4730 Å2
ΔGint-26 kcal/mol
Surface area37650 Å2
MethodPISA
3
C: Interferon inducible GTPase 1C
hetero molecules

D: Interferon inducible GTPase 1C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,98814
Polymers97,1242
Non-polymers1,86412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_444x-1,y-1,z-11
Buried area5380 Å2
ΔGint-46 kcal/mol
Surface area37480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.759, 100.245, 152.347
Angle α, β, γ (deg.)92.31, 101.24, 89.86
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Interferon inducible GTPase 1C / Interferon-gamma-inducible GTPase Ifgga2 protein / Predicted gene / EG240327


Mass: 48562.184 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Iigp1c, EG240327, Gm4951, Ifgga2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q3UED7
#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical
ChemComp-GSP / 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE


Mass: 539.246 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H16N5O13P3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.07 Å3/Da / Density % sol: 59.93 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 1M succinic acid pH 7.0, 0.1 M HEPES pH 7.0, and 1% (wt/vol) PEG-MME 2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 15, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.754→46.02 Å / Num. obs: 78604 / % possible obs: 88.1 % / Redundancy: 4.4 % / CC1/2: 0.979 / Net I/σ(I): 11.4
Reflection shellResolution: 2.754→2.8 Å / Num. unique obs: 2293 / CC1/2: 0.669

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Processing

Software
NameVersionClassification
REFMAC5.8.0349refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.75→46.02 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.88 / SU B: 13.441 / SU ML: 0.267 / Cross valid method: THROUGHOUT / ESU R Free: 0.456 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24659 3116 5.1 %RANDOM
Rwork0.20867 ---
obs0.21062 57883 68 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 54.965 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å20.03 Å2-0.03 Å2
2--0.02 Å2-0.05 Å2
3----0.08 Å2
Refinement stepCycle: 1 / Resolution: 2.75→46.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms19124 0 296 39 19459
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.01219827
X-RAY DIFFRACTIONr_bond_other_d0.0190.01617990
X-RAY DIFFRACTIONr_angle_refined_deg1.3631.64626793
X-RAY DIFFRACTIONr_angle_other_deg0.5351.55842015
X-RAY DIFFRACTIONr_dihedral_angle_1_deg652340
X-RAY DIFFRACTIONr_dihedral_angle_2_deg13.46810126
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.866103558
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0650.22960
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0222079
X-RAY DIFFRACTIONr_gen_planes_other0.0010.023945
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.2315.5629390
X-RAY DIFFRACTIONr_mcbond_other4.2315.5629390
X-RAY DIFFRACTIONr_mcangle_it6.878.32111720
X-RAY DIFFRACTIONr_mcangle_other6.878.32111721
X-RAY DIFFRACTIONr_scbond_it4.4375.88810437
X-RAY DIFFRACTIONr_scbond_other4.4385.88810435
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.2038.68715074
X-RAY DIFFRACTIONr_long_range_B_refined13.86784123
X-RAY DIFFRACTIONr_long_range_B_other13.86784123
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.754→2.825 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 52 -
Rwork0.308 1026 -
obs--16.26 %

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