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- PDB-9n2t: Structure of GDP-bound GM4951_D125G mutant -

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Basic information

Entry
Database: PDB / ID: 9n2t
TitleStructure of GDP-bound GM4951_D125G mutant
ComponentsInterferon inducible GTPase 1C
KeywordsLIPID BINDING PROTEIN / Lipid droplet associated protein / D125G mutant GM4951
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
GUANOSINE-5'-DIPHOSPHATE / Interferon inducible GTPase 1C
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)146,8426
Polymers145,5123
Non-polymers1,3303
Water23413
1
A: Interferon inducible GTPase 1C
hetero molecules

B: Interferon inducible GTPase 1C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,8954
Polymers97,0082
Non-polymers8862
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_445-x-1/2,y-1/2,-z1
Buried area3600 Å2
ΔGint-31 kcal/mol
Surface area36890 Å2
MethodPISA
2
C: Interferon inducible GTPase 1C
hetero molecules

C: Interferon inducible GTPase 1C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,8954
Polymers97,0082
Non-polymers8862
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area3580 Å2
ΔGint-31 kcal/mol
Surface area36430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)297.816, 58.909, 100.679
Angle α, β, γ (deg.)90.00, 92.03, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 48504.148 Da / Num. of mol.: 3 / Mutation: D125G
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-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / 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: 3.03 Å3/Da / Density % sol: 59.44 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 35% tacsimate pH 7.0

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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: Sep 21, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.6→50.01 Å / Num. obs: 51392 / % possible obs: 95.1 % / Redundancy: 4.2 % / CC1/2: 0.99 / Net I/σ(I): 16.56
Reflection shellResolution: 2.6→2.64 Å / Num. unique obs: 1867 / CC1/2: 0.584

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Processing

Software
NameVersionClassification
REFMAC5.8.0349refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→50.01 Å / Cor.coef. Fo:Fc: 0.902 / Cor.coef. Fo:Fc free: 0.878 / SU B: 10.963 / SU ML: 0.235 / Cross valid method: THROUGHOUT / ESU R Free: 0.4 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26689 1860 4.8 %RANDOM
Rwork0.23261 ---
obs0.23426 36665 71.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 48.823 Å2
Baniso -1Baniso -2Baniso -3
1--0.43 Å2-0 Å2-0.34 Å2
2--0.55 Å2-0 Å2
3----0.1 Å2
Refinement stepCycle: 1 / Resolution: 2.6→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9377 0 0 13 9390
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0129585
X-RAY DIFFRACTIONr_bond_other_d0.0190.0168645
X-RAY DIFFRACTIONr_angle_refined_deg1.2581.64212990
X-RAY DIFFRACTIONr_angle_other_deg0.5321.55620116
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.17351166
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.4131057
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.629101651
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0590.21455
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0210788
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021934
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_it4.0455.174679
X-RAY DIFFRACTIONr_mcbond_other4.0415.174679
X-RAY DIFFRACTIONr_mcangle_it6.4657.7345840
X-RAY DIFFRACTIONr_mcangle_other6.4647.7355841
X-RAY DIFFRACTIONr_scbond_it4.1765.2794906
X-RAY DIFFRACTIONr_scbond_other4.1765.284904
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.7267.817151
X-RAY DIFFRACTIONr_long_range_B_refined12.89895.58140527
X-RAY DIFFRACTIONr_long_range_B_other12.89895.58340525
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.602→2.669 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 38 -
Rwork0.313 624 -
obs--16.51 %

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