|Entry||Database: PDB / ID: 6u8n|
|Title||Human IMPDH2 treated with ATP, IMP, and NAD+. Fully extended filament segment reconstruction.|
|Components||Inosine-5'-monophosphate dehydrogenase 2|
|Keywords||BIOSYNTHETIC PROTEIN / metabolism / filament / allostery / adenine / guanine|
|Function / homology|
Function and homology information
lymphocyte proliferation / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase activity / IMP dehydrogenase / GMP biosynthetic process / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 / retina development in camera-type eye ...lymphocyte proliferation / 'de novo' XMP biosynthetic process / Purine ribonucleoside monophosphate biosynthesis / IMP dehydrogenase activity / IMP dehydrogenase / GMP biosynthetic process / peroxisomal membrane / GTP biosynthetic process / cellular response to interleukin-4 / retina development in camera-type eye / circadian rhythm / Potential therapeutics for SARS / secretory granule lumen / ficolin-1-rich granule lumen / nucleotide binding / Neutrophil degranulation / RNA binding / DNA binding / extracellular exosome / extracellular region / membrane / 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 / IMP dehydrogenase / GMP reductase domain / Domain in cystathionine beta-synthase and other proteins. / CBS domain / CBS domain / CBS domain profile. / Aldolase-type TIM barrel
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / INOSINIC ACID / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Inosine-5'-monophosphate dehydrogenase 2
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.29 Å|
|Authors||Johnson, M.C. / Kollman, J.M.|
|Funding support|| United States, 1items |
|Citation||Journal: Elife / Year: 2020|
Title: Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation.
Authors: Matthew C Johnson / Justin M Kollman /
Abstract: Inosine monophosphate dehydrogenase (IMPDH) mediates the first committed step in guanine nucleotide biosynthesis and plays important roles in cellular proliferation and the immune response. IMPDH ...Inosine monophosphate dehydrogenase (IMPDH) mediates the first committed step in guanine nucleotide biosynthesis and plays important roles in cellular proliferation and the immune response. IMPDH reversibly polymerizes in cells and tissues in response to changes in metabolic demand. Self-assembly of metabolic enzymes is increasingly recognized as a general mechanism for regulating activity, typically by stabilizing specific conformations of an enzyme, but the regulatory role of IMPDH filaments has remained unclear. Here, we report a series of human IMPDH2 cryo-EM structures in both active and inactive conformations. The structures define the mechanism of filament assembly, and reveal how filament-dependent allosteric regulation of IMPDH2 makes the enzyme less sensitive to feedback inhibition, explaining why assembly occurs under physiological conditions that require expansion of guanine nucleotide pools. Tuning sensitivity to an allosteric inhibitor distinguishes IMPDH from other metabolic filaments, and highlights the diversity of regulatory outcomes that can emerge from self-assembly.
|Structure viewer||Molecule: |
Downloads & links
I: Inosine-5'-monophosphate dehydrogenase 2
A: Inosine-5'-monophosphate dehydrogenase 2
J: Inosine-5'-monophosphate dehydrogenase 2
B: Inosine-5'-monophosphate dehydrogenase 2
K: Inosine-5'-monophosphate dehydrogenase 2
C: Inosine-5'-monophosphate dehydrogenase 2
L: Inosine-5'-monophosphate dehydrogenase 2
D: Inosine-5'-monophosphate dehydrogenase 2
M: Inosine-5'-monophosphate dehydrogenase 2
E: Inosine-5'-monophosphate dehydrogenase 2
N: Inosine-5'-monophosphate dehydrogenase 2
F: Inosine-5'-monophosphate dehydrogenase 2
O: Inosine-5'-monophosphate dehydrogenase 2
G: Inosine-5'-monophosphate dehydrogenase 2
P: Inosine-5'-monophosphate dehydrogenase 2
H: Inosine-5'-monophosphate dehydrogenase 2
Mass: 56480.500 Da / Num. of mol.: 16
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IMPDH2, IMPD2 / Production host: Escherichia coli (E. coli) / References: UniProt: P12268, IMP dehydrogenase
Mass: 507.181 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, 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: Human IMPDH2 treated with ATP, IMP, and NAD+. Fully extended filament segment reconstruction.|
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Escherichia coli (E. coli)|
|Buffer solution||pH: 7.5|
|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: 100 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Software||Name: PHENIX / Version: 1.14rc1_3161: / Classification: refinement|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Symmetry||Point symmetry: D4 (2x4 fold dihedral)|
|3D reconstruction||Resolution: 3.29 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 9124 / Symmetry type: POINT|
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