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- EMDB-24441: HUMAN IMPDH1 TREATED WITH GTP, IMP, AND NAD+ OCTAMER-CENTERED -

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Basic information

Entry
Database: EMDB / ID: EMD-24441
TitleHUMAN IMPDH1 TREATED WITH GTP, IMP, AND NAD+ OCTAMER-CENTERED
Map dataHUMAN IMPDH1 TREATED WITH GTP, IMP, AND NAD+ OCTAMER-CENTERED
Sample
  • Complex: Assembly interface of IMPDH1 filament bound to ATP, IMP, NAD+
    • Protein or peptide: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
  • Ligand: GUANOSINE-5'-TRIPHOSPHATEGuanosine triphosphate
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: INOSINIC ACID
Function / homology
Function and homology information


Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase activity / IMP dehydrogenase / GMP biosynthetic process / Azathioprine ADME / GTP biosynthetic process / azurophil granule lumen / secretory granule lumen / Potential therapeutics for SARS / ficolin-1-rich granule lumen ...Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase activity / IMP dehydrogenase / GMP biosynthetic process / Azathioprine ADME / GTP biosynthetic process / azurophil granule lumen / secretory granule lumen / Potential therapeutics for SARS / ficolin-1-rich granule lumen / nucleic acid binding / nucleotide binding / Neutrophil degranulation / DNA binding / RNA binding / extracellular region / metal ion binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Inosine-5'-monophosphate dehydrogenase / IMP dehydrogenase / GMP reductase, conserved site / IMP dehydrogenase / GMP reductase signature. / IMP dehydrogenase / GMP reductase domain / IMP dehydrogenase/GMP reductase / Domain in cystathionine beta-synthase and other proteins. / CBS domain / CBS domain / CBS domain profile. / Aldolase-type TIM barrel
Similarity search - Domain/homology
Inosine-5'-monophosphate dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsBurrell AL / Kollman JM
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM118396 United States
National Institutes of Health/National Eye Institute (NIH/NEI)EY030732 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM008268 United States
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: IMPDH1 retinal variants control filament architecture to tune allosteric regulation.
Authors: Anika L Burrell / Chuankai Nie / Meerit Said / Jacqueline C Simonet / David Fernández-Justel / Matthew C Johnson / Joel Quispe / Rubén M Buey / Jeffrey R Peterson / Justin M Kollman /
Abstract: Inosine-5'-monophosphate dehydrogenase (IMPDH), a key regulatory enzyme in purine nucleotide biosynthesis, dynamically assembles filaments in response to changes in metabolic demand. Humans have two ...Inosine-5'-monophosphate dehydrogenase (IMPDH), a key regulatory enzyme in purine nucleotide biosynthesis, dynamically assembles filaments in response to changes in metabolic demand. Humans have two isoforms: IMPDH2 filaments reduce sensitivity to feedback inhibition, while IMPDH1 assembly remains uncharacterized. IMPDH1 plays a unique role in retinal metabolism, and point mutants cause blindness. Here, in a series of cryogenic-electron microscopy structures we show that human IMPDH1 assembles polymorphic filaments with different assembly interfaces in extended and compressed states. Retina-specific splice variants introduce structural elements that reduce sensitivity to GTP inhibition, including stabilization of the extended filament form. Finally, we show that IMPDH1 disease mutations fall into two classes: one disrupts GTP regulation and the other has no effect on GTP regulation or filament assembly. These findings provide a foundation for understanding the role of IMPDH1 in retinal function and disease and demonstrate the diverse mechanisms by which metabolic enzyme filaments are allosterically regulated.
History
DepositionJul 14, 2021-
Header (metadata) releaseJan 12, 2022-
Map releaseJan 12, 2022-
UpdateFeb 2, 2022-
Current statusFeb 2, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.18
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 1.18
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7rfg
  • Surface level: 1.18
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7rfg
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_24441.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHUMAN IMPDH1 TREATED WITH GTP, IMP, AND NAD+ OCTAMER-CENTERED
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 320 pix.
= 336. Å
1.05 Å/pix.
x 320 pix.
= 336. Å
1.05 Å/pix.
x 320 pix.
= 336. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.05 Å
Density
Contour LevelBy AUTHOR: 1.18 / Movie #1: 1.18
Minimum - Maximum-5.958755 - 12.8236685
Average (Standard dev.)-1.5702378e-12 (±0.2953794)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 336.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.051.051.05
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z336.000336.000336.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ320320320
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-5.95912.824-0.000

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Supplemental data

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Sample components

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Entire : Assembly interface of IMPDH1 filament bound to ATP, IMP, NAD+

EntireName: Assembly interface of IMPDH1 filament bound to ATP, IMP, NAD+
Components
  • Complex: Assembly interface of IMPDH1 filament bound to ATP, IMP, NAD+
    • Protein or peptide: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
  • Ligand: GUANOSINE-5'-TRIPHOSPHATEGuanosine triphosphate
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: INOSINIC ACID

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Supramolecule #1: Assembly interface of IMPDH1 filament bound to ATP, IMP, NAD+

SupramoleculeName: Assembly interface of IMPDH1 filament bound to ATP, IMP, NAD+
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli) / Recombinant strain: BL21(DE3) / Recombinant plasmid: pSMT3
Molecular weightTheoretical: 55405 MDa

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Macromolecule #1: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1

MacromoleculeName: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1 / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO / EC number: IMP dehydrogenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.470652 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MADYLISGGT GYVPEDGLTA QQLFASADGL TYNDFLILPG FIDFIADEVD LTSALTRKIT LKTPLISSPM DTVTEADMAI AMALMGGIG FIHHNCTPEF QANEVRKVKK FEQGFITDPV VLSPSHTVGD VLEAKMRHGF SGIPITETGT MGSKLVGIVT S RDIDFLAE ...String:
MADYLISGGT GYVPEDGLTA QQLFASADGL TYNDFLILPG FIDFIADEVD LTSALTRKIT LKTPLISSPM DTVTEADMAI AMALMGGIG FIHHNCTPEF QANEVRKVKK FEQGFITDPV VLSPSHTVGD VLEAKMRHGF SGIPITETGT MGSKLVGIVT S RDIDFLAE KDHTTLLSEV MTPRIELVVA PAGVTLKEAN EILQRSKKGK LPIVNDCDEL VAIIARTDLK KNRDYPLASK DS QKQLLCG AAVGTREDDK YRLDLLTQAG VDVIVLDSSQ GNSVYQIAMV HYIKQKYPHL QVIGGNVVTA AQAKNLIDAG VDG LRVGMG CGSICITQEV MACGRPQGTA VYKVAEYARR FGVPIIADGG IQTVGHVVKA LALGASTVMM GSLLAATTEA PGEY FFSDG VRLKKYRGMG SLDAMEKSSS SQKRYFSEGD KVKIAQGVSG SIQDKGSIQK FVPYLIAGIQ HGCQDIGARS LSVLR SMMY SGELKFEKRT MSAQIEGGVH GLHSYEKRLY

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Macromolecule #2: GUANOSINE-5'-TRIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 16 / 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: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 8 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

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

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Macromolecule #4: INOSINIC ACID

MacromoleculeName: INOSINIC ACID / type: ligand / ID: 4 / Number of copies: 8 / Formula: IMP
Molecular weightTheoretical: 348.206 Da
Chemical component information

ChemComp-I:
INOSINIC ACID / Inosinic acid

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 42500

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