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- EMDB-44029: Cryo-EM structure of human uMtCK1 -

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Basic information

Entry
Database: EMDB / ID: EMD-44029
TitleCryo-EM structure of human uMtCK1
Map data
Sample
  • Complex: Octameric u-type mitochondrial creatine kinase
    • Protein or peptide: Creatine kinase U-type, mitochondrial
Keywordsmitochondrial creatine kinase / TRANSFERASE
Function / homology
Function and homology information


creatine kinase / Creatine metabolism / phosphocreatine biosynthetic process / creatine kinase activity / mitochondrial inner membrane / mitochondrion / ATP binding
Similarity search - Function
ATP:guanido phosphotransferase, N-terminal / ATP:guanido phosphotransferase, N-terminal domain superfamily / ATP:guanido phosphotransferase, N-terminal domain / Phosphagen kinase N-terminal domain profile. / ATP:guanido phosphotransferase active site / Phosphagen kinase active site signature. / ATP:guanido phosphotransferase / ATP:guanido phosphotransferase, catalytic domain / ATP:guanido phosphotransferase, C-terminal catalytic domain / Phosphagen kinase C-terminal domain profile. / Glutamine synthetase/guanido kinase, catalytic domain
Similarity search - Domain/homology
Creatine kinase U-type, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsDemir M / Koepping L / Zhao J / Sergienko E
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/Office of the DirectorOD026926 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA030199 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA251910 United States
CitationJournal: Structure / Year: 2025
Title: Structural basis for substrate binding, catalysis, and inhibition of cancer target mitochondrial creatine kinase by a covalent inhibitor.
Authors: Merve Demir / Laura Koepping / Ya Li / Lynn Fujimoto / Andrey Bobkov / Jianhua Zhao / Taro Hitosugi / Eduard Sergienko /
Abstract: Mitochondrial creatine kinases (MtCKs) are key players in maintaining energy homeostasis in cells that work with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. The ...Mitochondrial creatine kinases (MtCKs) are key players in maintaining energy homeostasis in cells that work with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. The inhibition of breast cancer growth by cyclocreatine targeting CKs indicates dependence of cancer cells on the "energy shuttle" for cell growth and survival. Hence, understanding key mechanistic features of creatine kinases and their inhibition plays an important role in the development of cancer therapeutics. Herein, we present mutational and structural investigations on understudied ubiquitous MtCK that showed closure of the loop comprising His61 is specific to and relies on creatine binding and mechanism of phosphoryl transfer depends on electrostatics of active site. We demonstrate that previously identified pan-CK covalent inhibitor CKi inhibit breast cancer cell proliferation; however, our biochemical and structural data indicated that inhibition by CKi is highly dependent on covalent link formation and conformational changes upon creatine binding are not observed.
History
DepositionMar 11, 2024-
Header (metadata) releaseFeb 12, 2025-
Map releaseFeb 12, 2025-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44029.png

Downloads & links

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Map

FileDownload / File: emd_44029.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 256 pix.
= 272.384 Å		1.06 Å/pix.
x 256 pix.
= 272.384 Å		1.06 Å/pix.
x 256 pix.
= 272.384 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.064 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.21749316 - 0.7117857
Average (Standard dev.)-0.00006778351 (±0.025521552)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 272.384 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_44029_msk_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

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Half map: #1

Fileemd_44029_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_44029_half_map_2.map
Projections & Slices
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Sample components

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Entire : Octameric u-type mitochondrial creatine kinase

EntireName: Octameric u-type mitochondrial creatine kinase
Components
  • Complex: Octameric u-type mitochondrial creatine kinase
    • Protein or peptide: Creatine kinase U-type, mitochondrial

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Supramolecule #1: Octameric u-type mitochondrial creatine kinase

SupramoleculeName: Octameric u-type mitochondrial creatine kinase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Creatine kinase U-type, mitochondrial

MacromoleculeName: Creatine kinase U-type, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO / EC number: creatine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 47.598719 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MGSSHHHHHH SSGLVPRGSH MENLYFQGAA SERRRLYPPS AEYPDLRKHN NCMASHLTPA VYARLCDKTT PTGWTLDQCI QTGVDNPGH PFIKTVGMVA GDEETYEVFA DLFDPVIQER HNGYDPRTMK HTTDLDASKI RSGYFDERYV LSSRVRTGRS I RGLSLPPA ...String:
MGSSHHHHHH SSGLVPRGSH MENLYFQGAA SERRRLYPPS AEYPDLRKHN NCMASHLTPA VYARLCDKTT PTGWTLDQCI QTGVDNPGH PFIKTVGMVA GDEETYEVFA DLFDPVIQER HNGYDPRTMK HTTDLDASKI RSGYFDERYV LSSRVRTGRS I RGLSLPPA CTRAERREVE RVVVDALSGL KGDLAGRYYR LSEMTEAEQQ QLIDDHFLFD KPVSPLLTAA GMARDWPDAR GI WHNNEKS FLIWVNEEDH TRVISMEKGG NMKRVFERFC RGLKEVERLI QERGWEFMWN ERLGYILTCP SNLGTGLRAG VHI KLPLLS KDSRFPKILE NLRLQKRGTG GVDTAATGGV FDISNLDRLG KSEVELVQLV IDGVNYLIDC ERRLERGQDI RIPT PVIHT KHGSSDYKDD DDK

UniProtKB: Creatine kinase U-type, mitochondrial

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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

Concentration1.0 mg/mL
BufferpH: 8
Component:
ConcentrationNameFormula
50.0 mMtris(hydroxymethyl)aminomethane
200.0 mMsodium chlorideNaCl
50.0 mMmagnesium chlorideMgCl2
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 34.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.1 µm / Nominal defocus min: 0.9 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3718445
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

1qk1

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2886327
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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