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- EMDB-52559: Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPD... -

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Basic information

Entry
Database: EMDB / ID: EMD-52559
TitleMycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) E-XMP* intermediate, compressed
Map dataLocScale primary viewing map
Sample
  • Complex: Octameric assembly of inosine monophosphate dehydrogenase reaction intermediate; E-XMP* in complex with NAD+
    • Protein or peptide: Inosine-5'-monophosphate dehydrogenase
  • Ligand: INOSINIC ACID
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
  • Ligand: POTASSIUM ION
  • Ligand: water
KeywordsOctamer / reaction intermediate / Purine metabolism / IMPDH / OXIDOREDUCTASE
Function / homology
Function and homology information


IMP dehydrogenase / IMP dehydrogenase activity / GMP biosynthetic process / GTP biosynthetic process / nucleotide binding / metal ion binding
Similarity search - Function
IMP dehydrogenase / GMP reductase, conserved site / IMP dehydrogenase / GMP reductase signature. / Inosine-5'-monophosphate dehydrogenase / IMP dehydrogenase/GMP reductase / IMP dehydrogenase / GMP reductase domain / IMP dehydrogenase / GMP reductase domain / Domain in cystathionine beta-synthase and other proteins. / CBS domain superfamily / CBS domain / CBS domain ...IMP dehydrogenase / GMP reductase, conserved site / IMP dehydrogenase / GMP reductase signature. / Inosine-5'-monophosphate dehydrogenase / IMP dehydrogenase/GMP reductase / IMP dehydrogenase / GMP reductase domain / IMP dehydrogenase / GMP reductase domain / Domain in cystathionine beta-synthase and other proteins. / CBS domain superfamily / CBS domain / CBS domain / CBS domain profile. / Aldolase-type TIM barrel
Similarity search - Domain/homology
Inosine-5'-monophosphate dehydrogenase
Similarity search - Component
Biological speciesMycolicibacterium smegmatis MC2 155 (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.73 Å
AuthorsBulvas O / Kouba T / Pichova I
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Union (EU)LX22NPO5103European Union
CitationJournal: J Struct Biol / Year: 2025
Title: Conformational landscape of the mycobacterial inosine 5'-monophosphate dehydrogenase octamerization interface.
Authors: Ondřej Bulvas / Zdeněk Knejzlík / Anatolij Filimoněnko / Tomáš Kouba / Iva Pichová /
Abstract: Inosine 5'-monophosphate dehydrogenase (IMPDH), a key enzyme in bacterial purine metabolism, plays an essential role in the biosynthesis of guanine nucleotides and shows promise as a target for ...Inosine 5'-monophosphate dehydrogenase (IMPDH), a key enzyme in bacterial purine metabolism, plays an essential role in the biosynthesis of guanine nucleotides and shows promise as a target for antimicrobial drug development. Despite its significance, the conformational dynamics and substrate-induced structural changes in bacterial IMPDH remain poorly understood, particularly with respect to its octameric assembly. Using cryo-EM, we present full-length structures of IMPDH from Mycobacterium smegmatis (MsmIMPDH) captured in a reaction intermediate state, revealing conformational changes upon substrate binding. The structures feature resolved flexible loops that coordinate the binding of the substrate, the cofactor, and the K ion. Our structural analysis identifies a novel octamerization interface unique to MsmIMPDH. Additionally, a previously unobserved barrel-like density suggests potential self-interactions within the C-terminal regions, hinting at a regulatory mechanism tied to assembly and function of the enzyme. These data provide insights into substrate-induced conformational dynamics and novel interaction interfaces in MsmIMPDH, potentially informing the development of IMPDH-targeted drugs.
History
DepositionJan 15, 2025-
Header (metadata) releaseMar 26, 2025-
Map releaseMar 26, 2025-
UpdateApr 2, 2025-
Current statusApr 2, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52559.png

Downloads & links

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Map

FileDownload / File: emd_52559.map.gz / Format: CCP4 / Size: 282.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocScale primary viewing map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 420 pix.
= 350.112 Å		0.83 Å/pix.
x 420 pix.
= 350.112 Å		0.83 Å/pix.
x 420 pix.
= 350.112 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8336 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.14
Minimum - Maximum-0.19541124 - 0.89241636
Average (Standard dev.)0.0016097167 (±0.019946426)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions420420420
Spacing420420420
CellA=B=C: 350.112 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_52559_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Additional map: Original map used for refinement and validation

Fileemd_52559_additional_1.map
AnnotationOriginal map used for refinement and validation
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_52559_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_52559_half_map_2.map
Projections & Slices
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Histogram

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Sample components

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Entire : Octameric assembly of inosine monophosphate dehydrogenase reactio...

EntireName: Octameric assembly of inosine monophosphate dehydrogenase reaction intermediate; E-XMP* in complex with NAD+
Components
  • Complex: Octameric assembly of inosine monophosphate dehydrogenase reaction intermediate; E-XMP* in complex with NAD+
    • Protein or peptide: Inosine-5'-monophosphate dehydrogenase
  • Ligand: INOSINIC ACID
  • Ligand: NICOTINAMIDE-ADENINE-DINUCLEOTIDE
  • Ligand: POTASSIUM ION
  • Ligand: water

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Supramolecule #1: Octameric assembly of inosine monophosphate dehydrogenase reactio...

SupramoleculeName: Octameric assembly of inosine monophosphate dehydrogenase reaction intermediate; E-XMP* in complex with NAD+
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mycolicibacterium smegmatis MC2 155 (bacteria)

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Macromolecule #1: Inosine-5'-monophosphate dehydrogenase

MacromoleculeName: Inosine-5'-monophosphate dehydrogenase / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO / EC number: IMP dehydrogenase
Source (natural)Organism: Mycolicibacterium smegmatis MC2 155 (bacteria) / Strain: MC2 155
Molecular weightTheoretical: 53.388988 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MSIAESSVPI AVPVPTGGDD PTKVAMLGLT FDDVLLLPAA SDVVPATADT SSQLTKRIRL RVPLVSSAMD TVTESRMAIA MARAGGMGV LHRNLPVAEQ AGQVETVKRS EAGMVTDPVT CSPDNTLAEV DAMCARFRIS GLPVVDDTGE LVGIITNRDM R FEVDQSKP ...String:
MSIAESSVPI AVPVPTGGDD PTKVAMLGLT FDDVLLLPAA SDVVPATADT SSQLTKRIRL RVPLVSSAMD TVTESRMAIA MARAGGMGV LHRNLPVAEQ AGQVETVKRS EAGMVTDPVT CSPDNTLAEV DAMCARFRIS GLPVVDDTGE LVGIITNRDM R FEVDQSKP VSEVMTKAPL ITAKEGVSAE AALGLLRRHK IEKLPIVDGH GKLTGLITVK DFVKTEQFPL STKDSDGRLL VG AAVGVGD DAWTRAMTLV DAGVDVLIVD TAHAHNRGVL DMVSRLKQAV GERVDVVGGN VATRAAAAAL VEAGADAVKV GVG PGSICT TRVVAGVGAP QITAILEAVA ACKPYGVPVI ADGGLQYSGD IAKALAAGAS TAMLGSLLAG TAESPGELIF VNGK QFKSY RGMGSLGAMQ GRGAAKSYSK DRYFQDDVLS EDKLVPEGIE GRVPFRGPLG TVIHQLTGGL RAAMGYTGSA TIEQL QQAQ FVQITAAGLK ESHPHDITMT VEAPNYYTR

UniProtKB: Inosine-5'-monophosphate dehydrogenase

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Macromolecule #2: INOSINIC ACID

MacromoleculeName: INOSINIC ACID / type: ligand / ID: 2 / Number of copies: 8 / Formula: IMP
Molecular weightTheoretical: 348.206 Da
Chemical component information

ChemComp-I:
INOSINIC ACID

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Macromolecule #3: NICOTINAMIDE-ADENINE-DINUCLEOTIDE

MacromoleculeName: NICOTINAMIDE-ADENINE-DINUCLEOTIDE / type: ligand / ID: 3 / Number of copies: 8 / Formula: NAD
Molecular weightTheoretical: 663.425 Da
Chemical component information

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM

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Macromolecule #4: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 4 / Number of copies: 8 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 80 / 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

BufferpH: 7.5
Component:
ConcentrationFormulaName
50.0 mMHEPES2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethane-1-sulfonic acid
200.0 mMKClPotassium chloride
5.0 mMDTTDithiothreitol
32.0 mMMgCl2Magnesium chloride
10.0 mMIMPInosine monophosphate
10.0 mMNADNicotinamide adenine dinucleotide
10.0 mMATPAdenosine triphosphate

Details: 50 mM HEPES (pH 7.5), 200 mM KCl, 5 mM DTT, 32 mM MgCl2 Ligand: 10 mM ATP + 10 mM IMP + 10 mM NAD
GridModel: Quantifoil R2/1 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 8691 / Average exposure time: 2.0 sec. / Average electron dose: 40.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.2 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 165000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4833002
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7pji

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.73 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 124968
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8qqv


Chain - Source name: PDB / Chain - Initial model type: experimental model
DetailsInitial fitting was done in UCSF ChimeraX. Model refinement was done by iterative cycles of manual fitting with Coot and ISOLDE and automated fitting with phenix.real_space_refine.
RefinementProtocol: RIGID BODY FIT / Overall B value: 37.48 / Target criteria: CC coefficient
Output model

PDB-9i0k:
Mycobacterium smegmatis inosine monophosphate dehydrogenase (IMPDH) E-XMP* intermediate, compressed

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