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- EMDB-45803: Structural basis of BAK sequestration by MCL-1 and consequences f... -

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Basic information

Entry
Database: EMDB / ID: EMD-45803
TitleStructural basis of BAK sequestration by MCL-1 and consequences for apoptosis initiation
Map data
Sample
  • Complex: hetero-tetrameric Complex of Sab11M heavy and long chain, MBP_MCL1 fusion protein, and BAK-BH3
    • Protein or peptide: Induced myeloid leukemia cell differentiation protein Mcl-1
    • Protein or peptide: Bcl-2 homologous antagonist/killer
    • Protein or peptide: Synthetic antibody, Fab fragment, Heavy Chain
    • Protein or peptide: Synthetic antibody, Fab fragment, Light Chain
KeywordsAnti-apoptosis / Mitochondrial poration / BCL-2 family / Cell fate / APOPTOSIS
Function / homology
Function and homology information


Activation and oligomerization of BAK protein / response to mycotoxin / BH domain binding / B cell negative selection / BAK complex / apoptotic process involved in blood vessel morphogenesis / negative regulation of endoplasmic reticulum calcium ion concentration / response to fungus / limb morphogenesis / Release of apoptotic factors from the mitochondria ...Activation and oligomerization of BAK protein / response to mycotoxin / BH domain binding / B cell negative selection / BAK complex / apoptotic process involved in blood vessel morphogenesis / negative regulation of endoplasmic reticulum calcium ion concentration / response to fungus / limb morphogenesis / Release of apoptotic factors from the mitochondria / post-embryonic camera-type eye morphogenesis / endocrine pancreas development / establishment or maintenance of transmembrane electrochemical gradient / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / B cell apoptotic process / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / endoplasmic reticulum calcium ion homeostasis / regulation of mitochondrial membrane permeability / calcium ion transport into cytosol / response to UV-C / fibroblast apoptotic process / mitochondrial fusion / Bcl-2 family protein complex / myeloid cell homeostasis / porin activity / thymocyte apoptotic process / positive regulation of calcium ion transport into cytosol / pore complex / negative regulation of release of cytochrome c from mitochondria / positive regulation of IRE1-mediated unfolded protein response / positive regulation of release of cytochrome c from mitochondria / vagina development / B cell homeostasis / positive regulation of proteolysis / blood vessel remodeling / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / Pyroptosis / cellular response to unfolded protein / animal organ regeneration / extrinsic apoptotic signaling pathway in absence of ligand / heat shock protein binding / intrinsic apoptotic signaling pathway / release of cytochrome c from mitochondria / regulation of mitochondrial membrane potential / epithelial cell proliferation / response to gamma radiation / establishment of localization in cell / positive regulation of protein-containing complex assembly / apoptotic signaling pathway / : / response to hydrogen peroxide / cellular response to mechanical stimulus / intrinsic apoptotic signaling pathway in response to DNA damage / cellular response to UV / protein-folding chaperone binding / channel activity / response to ethanol / mitochondrial outer membrane / transmembrane transporter binding / regulation of cell cycle / positive regulation of apoptotic process / protein heterodimerization activity / response to xenobiotic stimulus / negative regulation of cell population proliferation / negative regulation of gene expression / apoptotic process / protein-containing complex binding / endoplasmic reticulum / protein homodimerization activity / mitochondrion / metal ion binding / identical protein binding / cytosol
Similarity search - Function
Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Apoptosis regulator, Bcl-2 family BH3 motif signature. / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2, BH2 motif, conserved site / Apoptosis regulator, Bcl-2 family BH2 motif signature. / Bcl-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like / Bcl-2, Bcl-2 homology region 1-3 ...Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Apoptosis regulator, Bcl-2 family BH3 motif signature. / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2, BH2 motif, conserved site / Apoptosis regulator, Bcl-2 family BH2 motif signature. / Bcl-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like / Bcl-2, Bcl-2 homology region 1-3 / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily
Similarity search - Domain/homology
Bcl-2 homologous antagonist/killer
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsUchikawa E / Myasnikov A / Dey R / Moldoveanu T
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM129470 United States
CitationJournal: Mol Cell / Year: 2025
Title: Structural basis of BAK sequestration by MCL-1 in apoptosis.
Authors: Shagun Srivastava / Giridhar Sekar / Adedolapo Ojoawo / Anup Aggarwal / Elisabeth Ferreira / Emiko Uchikawa / Meek Yang / Christy R Grace / Raja Dey / Yi-Lun Lin / Cristina D Guibao / ...Authors: Shagun Srivastava / Giridhar Sekar / Adedolapo Ojoawo / Anup Aggarwal / Elisabeth Ferreira / Emiko Uchikawa / Meek Yang / Christy R Grace / Raja Dey / Yi-Lun Lin / Cristina D Guibao / Seetharaman Jayaraman / Somnath Mukherjee / Anthony A Kossiakoff / Bin Dong / Alexander Myasnikov / Tudor Moldoveanu /
Abstract: Apoptosis controls cell fate, ensuring tissue homeostasis and promoting disease when dysregulated. The rate-limiting step in apoptosis is mitochondrial poration by the effector B cell lymphoma 2 (BCL- ...Apoptosis controls cell fate, ensuring tissue homeostasis and promoting disease when dysregulated. The rate-limiting step in apoptosis is mitochondrial poration by the effector B cell lymphoma 2 (BCL-2) family proteins BAK and BAX, which are activated by initiator BCL-2 homology 3 (BH3)-only proteins (e.g., BIM) and inhibited by guardian BCL-2 family proteins (e.g., MCL-1). We integrated structural, biochemical, and pharmacological approaches to characterize the human prosurvival MCL-1:BAK complex assembled from their BCL-2 globular core domains. We reveal a canonical interaction with BAK BH3 bound to the hydrophobic groove of MCL-1 and disordered and highly dynamic BAK regions outside the complex interface. We predict similar conformations of activated effectors in complex with other guardians or effectors. The MCL-1:BAK complex is a major cancer drug target. We show that MCL-1 inhibitors are inefficient in neutralizing the MCL-1:BAK complex, requiring high doses to initiate apoptosis. Our study underscores the need to design superior clinical candidate MCL-1 inhibitors.
History
DepositionJul 18, 2024-
Header (metadata) releaseJun 4, 2025-
Map releaseJun 4, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45803.png

Downloads & links

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Map

FileDownload / File: emd_45803.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.45 Å/pix.
x 256 pix.
= 371.712 Å		1.45 Å/pix.
x 256 pix.
= 371.712 Å		1.45 Å/pix.
x 256 pix.
= 371.712 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.452 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.009
Minimum - Maximum-0.023974746 - 0.04778508
Average (Standard dev.)0.000025617737 (±0.000621359)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 371.712 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_45803_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_45803_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : hetero-tetrameric Complex of Sab11M heavy and long chain, MBP_MCL...

EntireName: hetero-tetrameric Complex of Sab11M heavy and long chain, MBP_MCL1 fusion protein, and BAK-BH3
Components
  • Complex: hetero-tetrameric Complex of Sab11M heavy and long chain, MBP_MCL1 fusion protein, and BAK-BH3
    • Protein or peptide: Induced myeloid leukemia cell differentiation protein Mcl-1
    • Protein or peptide: Bcl-2 homologous antagonist/killer
    • Protein or peptide: Synthetic antibody, Fab fragment, Heavy Chain
    • Protein or peptide: Synthetic antibody, Fab fragment, Light Chain

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Supramolecule #1: hetero-tetrameric Complex of Sab11M heavy and long chain, MBP_MCL...

SupramoleculeName: hetero-tetrameric Complex of Sab11M heavy and long chain, MBP_MCL1 fusion protein, and BAK-BH3
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Induced myeloid leukemia cell differentiation protein Mcl-1

MacromoleculeName: Induced myeloid leukemia cell differentiation protein Mcl-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 57.152789 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: KIEEGKLVIW INGDKGYNGL AEVGKKFEKD TGIKVTVEHP DKLEEKFPQV AATGDGPDII FWAHDRFGGY AQSGLLAEIT PDKAFQDKL YPFTWDAVRY NGKLIAYPIA VEALSLIYNK DLLPNPPKTW EEIPALDKEL KAKGKSALMF NLQEPYFTWP L IAADGGYA ...String:
KIEEGKLVIW INGDKGYNGL AEVGKKFEKD TGIKVTVEHP DKLEEKFPQV AATGDGPDII FWAHDRFGGY AQSGLLAEIT PDKAFQDKL YPFTWDAVRY NGKLIAYPIA VEALSLIYNK DLLPNPPKTW EEIPALDKEL KAKGKSALMF NLQEPYFTWP L IAADGGYA FKYENGKYDI KDVGVDNAGA KAGLTFLVDL IKNKHMNADT DYSIAEAAFN KGETAMTING PWAWSNIDTS KV NYGVTVL PTFKGQPSKP FVGVLSAGIN AASPNKELAK EFLENYLLTD EGLEAVNKDK PLGAVALKSY EEELAKDPRI AAT MENAQK GEIMPNIPQM SAFWYAVRTA VINAASGRQT VDEALKDAQT IIELYRQSLE IISRYLREQA TGAADTAPMG RSGA TSRKA LETLRRVGDG VQRNHETAFQ GMLRKLDIKN EDDVKSLSRV MIHVFSDGVT NWGRIVTLIS FGAFVAKHLK TINQE SAIE PLAESITDVL VRTKRDWLVK QRGWDGFVEF F

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Macromolecule #2: Bcl-2 homologous antagonist/killer

MacromoleculeName: Bcl-2 homologous antagonist/killer / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.366679 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
STMGQVGRQL AIIGDDINRR Y

UniProtKB: Bcl-2 homologous antagonist/killer

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Macromolecule #3: Synthetic antibody, Fab fragment, Heavy Chain

MacromoleculeName: Synthetic antibody, Fab fragment, Heavy Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.534371 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EVQLVESGGG LVQPGGSLRL SCAASGFNLS SSSIHWVRQA PGKGLEWVAS IYSYYGSTSY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCARE YHSYWSYSWW PRVGLDYWGQ GTLVTVSSAS TKGPSVFPLA PASKSAAAAT AALGCLVKDY F PEPVTVSW ...String:
EVQLVESGGG LVQPGGSLRL SCAASGFNLS SSSIHWVRQA PGKGLEWVAS IYSYYGSTSY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCARE YHSYWSYSWW PRVGLDYWGQ GTLVTVSSAS TKGPSVFPLA PASKSAAAAT AALGCLVKDY F PEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SC

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Macromolecule #4: Synthetic antibody, Fab fragment, Light Chain

MacromoleculeName: Synthetic antibody, Fab fragment, Light Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.109719 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: AQMTQSPSSL SASVGDRVTI TCRASQSVSS AVAWYQQKPG KAPKLLIYSA SSLYSGVPSR FSGSRSGTDF TLTISSLQPE DFATYYCQQ ASLTALLTFG QGTKVEIKRT VAAPSVFIFP PSDSQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
AQMTQSPSSL SASVGDRVTI TCRASQSVSS AVAWYQQKPG KAPKLLIYSA SSLYSGVPSR FSGSRSGTDF TLTISSLQPE DFATYYCQQ ASLTALLTFG QGTKVEIKRT VAAPSVFIFP PSDSQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5lof

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 150154
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: MAXIMUM LIKELIHOOD

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