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- PDB-8e8o: Cryo-EM structure of human ME3 in the presence of citrate -

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Basic information

Entry
Database: PDB / ID: 8e8o
TitleCryo-EM structure of human ME3 in the presence of citrate
ComponentsNADP-dependent malic enzyme, mitochondrial
KeywordsHYDROLASE / ME1 / ME2 / ME3 / NAD(P)-dependent malic enzymes / integrated structural techniques / crystal structures / cryo-EM structures / drug discovery / allosteric mechanism
Function / homology
Function and homology information


malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) / malic enzyme activity / oxygen metabolic process / malate dehydrogenase (decarboxylating) (NADP+) activity / oxaloacetate decarboxylase activity / malate metabolic process / pyruvate metabolic process / Pyruvate metabolism / NADP+ binding / aerobic respiration ...malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) / malic enzyme activity / oxygen metabolic process / malate dehydrogenase (decarboxylating) (NADP+) activity / oxaloacetate decarboxylase activity / malate metabolic process / pyruvate metabolic process / Pyruvate metabolism / NADP+ binding / aerobic respiration / NAD binding / mitochondrial matrix / mitochondrion / metal ion binding
Similarity search - Function
Malic enzyme, conserved site / Malic enzymes signature. / Malic oxidoreductase / Malic enzyme, N-terminal domain / Malic enzyme, N-terminal domain / Malic enzyme, NAD-binding / Malic enzyme, N-terminal domain superfamily / Malic enzyme, N-terminal domain / Malic enzyme, NAD binding domain / Malic enzyme, NAD binding domain ...Malic enzyme, conserved site / Malic enzymes signature. / Malic oxidoreductase / Malic enzyme, N-terminal domain / Malic enzyme, N-terminal domain / Malic enzyme, NAD-binding / Malic enzyme, N-terminal domain superfamily / Malic enzyme, N-terminal domain / Malic enzyme, NAD binding domain / Malic enzyme, NAD binding domain / Aminoacid dehydrogenase-like, N-terminal domain superfamily / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / NADP-dependent malic enzyme, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.77 Å
AuthorsYu, X. / Grell, T.A.J. / Shaffer, P.L. / Steele, R. / Sharma, S. / Thompson, A.A. / Tresadern, G. / Ortiz-Meoz, R.F. / Mason, M. / Gomez-Tamayo, J.C. ...Yu, X. / Grell, T.A.J. / Shaffer, P.L. / Steele, R. / Sharma, S. / Thompson, A.A. / Tresadern, G. / Ortiz-Meoz, R.F. / Mason, M. / Gomez-Tamayo, J.C. / Riley, D. / Wagner, M.V. / Wadia, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Heliyon / Year: 2022
Title: Integrative structural and functional analysis of human malic enzyme 3: A potential therapeutic target for pancreatic cancer.
Authors: Tsehai A J Grell / Mark Mason / Aaron A Thompson / Jose Carlos Gómez-Tamayo / Daniel Riley / Michelle V Wagner / Ruth Steele / Rodrigo F Ortiz-Meoz / Jay Wadia / Paul L Shaffer / Gary ...Authors: Tsehai A J Grell / Mark Mason / Aaron A Thompson / Jose Carlos Gómez-Tamayo / Daniel Riley / Michelle V Wagner / Ruth Steele / Rodrigo F Ortiz-Meoz / Jay Wadia / Paul L Shaffer / Gary Tresadern / Sujata Sharma / Xiaodi Yu /
Abstract: Malic enzymes (ME1, ME2, and ME3) are involved in cellular energy regulation, redox homeostasis, and biosynthetic processes, through the production of pyruvate and reducing agent NAD(P)H. Recent ...Malic enzymes (ME1, ME2, and ME3) are involved in cellular energy regulation, redox homeostasis, and biosynthetic processes, through the production of pyruvate and reducing agent NAD(P)H. Recent studies have implicated the third and least well-characterized isoform, mitochondrial NADP-dependent malic enzyme 3 (ME3), as a therapeutic target for pancreatic cancers. Here, we utilized an integrated structure approach to determine the structures of ME3 in various ligand-binding states at near-atomic resolutions. ME3 is captured in the open form existing as a stable tetramer and its dynamic Domain C is critical for activity. Catalytic assay results reveal that ME3 is a non-allosteric enzyme and does not require modulators for activity while structural analysis suggests that the inner stability of ME3 Domain A relative to ME2 disables allostery in ME3. With structural information available for all three malic enzymes, the foundation has been laid to understand the structural and biochemical differences of these enzymes and could aid in the development of specific malic enzyme small molecule drugs.
History
DepositionAug 25, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 8, 2023Provider: repository / Type: Initial release
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Revision 1.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.2Jun 4, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
Item: _em_admin.last_update / _em_software.name / _pdbx_entry_details.has_protein_modification
Revision 1.1Jun 4, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NADP-dependent malic enzyme, mitochondrial
B: NADP-dependent malic enzyme, mitochondrial
C: NADP-dependent malic enzyme, mitochondrial
D: NADP-dependent malic enzyme, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)271,5798
Polymers268,6054
Non-polymers2,9744
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
NADP-dependent malic enzyme, mitochondrial / NADP-ME / Malic enzyme 3


Mass: 67151.250 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ME3 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q16798, malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+)
#2: Chemical
ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Cryo-EM structure human ME3 in the presence of NADP / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 174701 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00718100
ELECTRON MICROSCOPYf_angle_d0.6724560
ELECTRON MICROSCOPYf_dihedral_angle_d4.7910840
ELECTRON MICROSCOPYf_chiral_restr0.0472744
ELECTRON MICROSCOPYf_plane_restr0.0043152

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