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- EMDB-27936: Cryo-EM structure of Apo form ME3 -

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Basic information

Entry
Database: EMDB / ID: EMD-27936
TitleCryo-EM structure of Apo form ME3
Map dataEM summary map without sharpen
Sample
  • Complex: Cryo-EM structure of Apo ME3
    • Protein or peptide: NADP-dependent malic enzyme, mitochondrial
Function / homology
Function and homology information


oxygen metabolic process / malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) / malate dehydrogenase (decarboxylating) (NADP+) activity / malic enzyme activity / oxaloacetate decarboxylase activity / Citric acid cycle (TCA cycle) / malate metabolic process / pyruvate metabolic process / NADP+ binding / aerobic respiration ...oxygen metabolic process / malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) / malate dehydrogenase (decarboxylating) (NADP+) activity / malic enzyme activity / oxaloacetate decarboxylase activity / Citric acid cycle (TCA cycle) / malate metabolic process / pyruvate metabolic process / 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-dependent malic enzyme, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.51 Å
AuthorsYu X / Grell TAJ / Shaffer PL / Steele R / Sharma S / Thompson AA / Tresadern G / Ortiz-Meoz RF / Mason M / Gomez-Tamayo JC ...Yu X / Grell TAJ / Shaffer PL / Steele R / Sharma S / Thompson AA / Tresadern G / Ortiz-Meoz RF / Mason M / Gomez-Tamayo JC / Riley D / Wagner MV / Wadia J
Funding support1 items
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 23, 2022-
Header (metadata) releaseFeb 8, 2023-
Map releaseFeb 8, 2023-
UpdateFeb 8, 2023-
Current statusFeb 8, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27936.png

Downloads & links

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Map

FileDownload / File: emd_27936.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationEM summary map without sharpen
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 0.0214
Minimum - Maximum-0.02475565 - 0.076310426
Average (Standard dev.)0.0003285332 (±0.004088454)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 208.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27936_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Additional map: Masked and Sharpened EM map

Fileemd_27936_additional_1.map
AnnotationMasked and Sharpened EM map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Additional map: Sharpened EM map

Fileemd_27936_additional_2.map
AnnotationSharpened EM map
Projections & Slices
AxesZYX

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Histogram

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Half map: #1

Fileemd_27936_half_map_1.map
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Half map: #2

Fileemd_27936_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of Apo ME3

EntireName: Cryo-EM structure of Apo ME3
Components
  • Complex: Cryo-EM structure of Apo ME3
    • Protein or peptide: NADP-dependent malic enzyme, mitochondrial

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Supramolecule #1: Cryo-EM structure of Apo ME3

SupramoleculeName: Cryo-EM structure of Apo ME3 / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: NADP-dependent malic enzyme, mitochondrial

MacromoleculeName: NADP-dependent malic enzyme, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
EC number: malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+)
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 67.15125 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGAALGTGTR LAPWPGRACG ALPRWTPTAP AQGCHSKPGP ARPVPLKKRG YDVTRNPHLN KGMAFTLEER LQLGIHGLIP PCFLSQDVQ LLRIMRYYER QQSDLDKYII LMTLQDRNEK LFYRVLTSDV EKFMPIVYTP TVGLACQHYG LTFRRPRGLF I TIHDKGHL ...String:
MGAALGTGTR LAPWPGRACG ALPRWTPTAP AQGCHSKPGP ARPVPLKKRG YDVTRNPHLN KGMAFTLEER LQLGIHGLIP PCFLSQDVQ LLRIMRYYER QQSDLDKYII LMTLQDRNEK LFYRVLTSDV EKFMPIVYTP TVGLACQHYG LTFRRPRGLF I TIHDKGHL ATMLNSWPED NIKAVVVTDG ERILGLGDLG CYGMGIPVGK LALYTACGGV NPQQCLPVLL DVGTNNEELL RD PLYIGLK HQRVHGKAYD DLLDEFMQAV TDKFGINCLI QFEDFANANA FRLLNKYRNK YCMFNDDIQG TASVAVAGIL AAL RITKNK LSNHVFVFQG AGEAAMGIAH LLVMALEKEG VPKAEATRKI WMVDSKGLIV KGRSHLNHEK EMFAQDHPEV NSLE EVVRL VKPTAIIGVA AIAGAFTEQI LRDMASFHER PIIFALSNPT SKAECTAEKC YRVTEGRGIF ASGSPFKSVT LEDGK TFIP GQGNNAYVFP GVALGVIAGG IRHIPDEIFL LTAEQIAQEV SEQHLSQGRL YPPLSTIRDV SLRIAIKVLD YAYKHN LAS YYPEPKDKEA FVRSLVYTPD YDSFTLDSYT WPKEAMNVQT V

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 45.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.51 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 473519
FSC plot (resolution estimation)

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