|Entry||Database: PDB / ID: 7rfi|
|Title||HUMAN RETINAL VARIANT IMPDH1(595) TREATED WITH GTP, ATP, IMP, NAD+, INTERFACE-CENTERED|
|Components||Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1|
|Keywords||OXIDOREDUCTASE / METABOLISM / FILAMENT / ALLOSTERY / ADENINE|
|Function / homology||IMP dehydrogenase / GUANOSINE-5'-TRIPHOSPHATE / INOSINIC ACID / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1|
Function and homology information
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å|
|Model details||FILAMENT ASSEMBLY INTERFACE RECONSTRUCTION|
|Authors||Burrell, A.L. / Kollman, J.M.|
|Funding support|| United States, 3items |
|Citation||Journal: 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.
|Structure viewer||Molecule: |
Downloads & links
A: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
B: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
C: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
D: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
E: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
F: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
G: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
H: Isoform 5 of Inosine-5'-monophosphate dehydrogenase 1
Mass: 66225.719 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: P20839-5, IMP dehydrogenase
Mass: 523.180 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: GTP, energy-carrying molecule*YM
Mass: 348.206 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H13N4O8P / Feature type: SUBJECT OF INVESTIGATION
Mass: 663.425 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
|Has ligand of interest||Y|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction|
|Component||Name: Assembly interface of IMPDH1 filament bound to ATP, IMP, NAD+|
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
|Molecular weight||Value: 55405 MDa / Experimental value: NO|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Escherichia coli (E. coli) / Strain: BL21(DE3) / Plasmid: pSMT3|
|Buffer solution||pH: 7|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|3D reconstruction||Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 68282 / Symmetry type: POINT|
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