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- PDB-7rer: HUMAN IMPDH1 TREATED WITH ATP, IMP, AND NAD+ -

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Basic information

Entry
Database: PDB / ID: 7rer
TitleHUMAN IMPDH1 TREATED WITH ATP, IMP, AND NAD+
ComponentsIsoform 5 of Inosine-5'-monophosphate dehydrogenase 1
KeywordsOXIDOREDUCTASE / METABOLISM / FILAMENT / ALLOSTERY / ADENINE
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 / Potential therapeutics for SARS / secretory granule lumen / nucleic acid binding ...Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase activity / IMP dehydrogenase / GMP biosynthetic process / Azathioprine ADME / GTP biosynthetic process / azurophil granule lumen / Potential therapeutics for SARS / secretory granule lumen / nucleic acid binding / ficolin-1-rich granule lumen / nucleotide binding / Neutrophil degranulation / RNA binding / DNA binding / extracellular region / metal ion binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Inosine-5'-monophosphate dehydrogenase / IMP dehydrogenase / GMP reductase signature. / IMP dehydrogenase / GMP reductase, conserved site / 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
INOSINIC ACID / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Inosine-5'-monophosphate dehydrogenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
Model detailsFILAMENT ASSEMBLY INTERFACE RECONSTRUCTION
AuthorsBurrell, A.L. / Kollman, J.M.
Funding support United States, 3items
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 13, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 26, 2022Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 2, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Assembly

Deposited unit
A: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
D: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
C: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
B: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
E: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
H: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
G: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
F: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)451,85824
Polymers443,7658
Non-polymers8,09316
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1 / IMP dehydrogenase 1 / IMPD 1 / IMPDH 1 / IMPDH-I


Mass: 55470.652 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IMPDH1, IMPD1 / Plasmid: PSMT3 / Production host: Escherichia coli BL21(DE3) (unknown) / References: UniProt: P20839, IMP dehydrogenase
#2: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Nicotinamide adenine dinucleotide


Mass: 663.425 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
#3: Chemical
ChemComp-IMP / INOSINIC ACID / Inosinic acid


Mass: 348.206 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H13N4O8P / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Assembly interface of IMPDH1 filament bound to ATP, IMP, NAD+
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 55405 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: BL21(DE3) / Plasmid: pSMT3
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 103500 / Symmetry type: POINT

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