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- EMDB-24442: HUMAN RETINAL VARIANT IMPDH1(595) TREATED WITH ATP, OCTAMER-CENTERED -

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Basic information

Entry
Database: EMDB / ID: EMD-24442
TitleHUMAN RETINAL VARIANT IMPDH1(595) TREATED WITH ATP, OCTAMER-CENTERED
Map dataHUMAN RETINAL VARIANT IMPDH1(595) TREATED WITH ATP, 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: ADENOSINE-5'-TRIPHOSPHATE
KeywordsMETABOLISM / FILAMENT / ALLOSTERY / ADENINE / OXIDOREDUCTASE
Function / homologyIMP dehydrogenase / Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
Function and homology information
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 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-
UpdateJun 5, 2024-
Current statusJun 5, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1
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  • Surface view colored by cylindrical radius
  • Surface level: 1
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  • Surface view with fitted model
  • Atomic models: PDB-7rfh
  • Surface level: 1
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7rfh
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

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Map

FileDownload / File: emd_24442.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHUMAN RETINAL VARIANT IMPDH1(595) TREATED WITH ATP, OCTAMER-CENTERED
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (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: 1.0 / Movie #1: 1
Minimum - Maximum-6.541242 - 11.223599
Average (Standard dev.)0.00000000000028 (±0.27874717)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
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/S321
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-6.54111.2240.000

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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: ADENOSINE-5'-TRIPHOSPHATE

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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)
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: 63.407324 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MEGPLTPPPL QGGGAAAVPE PGARQHPGHE TAAQRYSARL LQAGYEPESM ADYLISGGTG YVPEDGLTAQ QLFASADGLT YNDFLILPG FIDFIADEVD LTSALTRKIT LKTPLISSPM DTVTEADMAI AMALMGGIGF IHHNCTPEFQ ANEVRKVKKF E QGFITDPV ...String:
MEGPLTPPPL QGGGAAAVPE PGARQHPGHE TAAQRYSARL LQAGYEPESM ADYLISGGTG YVPEDGLTAQ QLFASADGLT YNDFLILPG FIDFIADEVD LTSALTRKIT LKTPLISSPM DTVTEADMAI AMALMGGIGF IHHNCTPEFQ ANEVRKVKKF E QGFITDPV VLSPSHTVGD VLEAKMRHGF SGIPITETGT MGSKLVGIVT SRDIDFLAEK DHTTLLSEVM TPRIELVVAP AG VTLKEAN EILQRSKKGK LPIVNDCDEL VAIIARTDLK KNRDYPLASK DSQKQLLCGA AVGTREDDKY RLDLLTQAGV DVI VLDSSQ GNSVYQIAMV HYIKQKYPHL QVIGGNVVTA AQAKNLIDAG VDGLRVGMGC GSICITQEVM ACGRPQGTAV YKVA EYARR FGVPIIADGG IQTVGHVVKA LALGASTVMM GSLLAATTEA PGEYFFSDGV RLKKYRGMGS LDAMEKSSSS QKRYF SEGD KVKIAQGVSG SIQDKGSIQK FVPYLIAGIQ HGCQDIGARS LSVLRSMMYS GELKFEKRTM SAQIEGGVHG LHSYTF LPF TKSGCTEDSG GGRGGGGDAP QCPLLGTASL HN

UniProtKB: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1

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Macromolecule #2: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 16 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

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

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

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Image processing

Startup modelType of model: EMDB MAP
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 11476
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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