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- PDB-9cph: Structural basis of BAK sequestration by MCL-1 and consequences f... -

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Basic information

Entry
Database: PDB / ID: 9cph
TitleStructural basis of BAK sequestration by MCL-1 and consequences for apoptosis initiation
Components
  • Bcl-2 homologous antagonist/killer
  • Induced myeloid leukemia cell differentiation protein Mcl-1
  • Synthetic antibody, Fab fragment, Heavy Chain
  • Synthetic antibody, Fab fragment, Light Chain
KeywordsAPOPTOSIS / Anti-apoptosis / Mitochondrial poration / BCL-2 family / Cell fate
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
alpha-maltose / Bcl-2 homologous antagonist/killer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsUchikawa, E. / Myasnikov, A. / Dey, R. / Moldoveanu, T.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 4, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Induced myeloid leukemia cell differentiation protein Mcl-1
B: Bcl-2 homologous antagonist/killer
H: Synthetic antibody, Fab fragment, Heavy Chain
L: Synthetic antibody, Fab fragment, Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,5065
Polymers107,1644
Non-polymers3421
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 57152.789 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#2: Protein/peptide Bcl-2 homologous antagonist/killer / Apoptosis regulator BAK / Bcl-2-like protein 7 / Bcl2-L-7


Mass: 2366.679 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BAK1, BAK, BCL2L7, CDN1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q16611
#3: Antibody Synthetic antibody, Fab fragment, Heavy Chain


Mass: 24534.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#4: Antibody Synthetic antibody, Fab fragment, Light Chain


Mass: 23109.719 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#5: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose


Type: oligosaccharide, Oligosaccharide / Class: Nutrient / Mass: 342.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: oligosaccharide / References: alpha-maltose
DescriptorTypeProgram
DGlcpa1-4DGlcpa1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1a_1-5]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][a-D-Glcp]{[(4+1)][a-D-Glcp]{}}LINUCSPDB-CARE
Has ligand of interestY
Has protein modificationY

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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: hetero-tetrameric Complex of Sab11M heavy and long chain, MBP_MCL1 fusion protein, and BAK-BH3
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7
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: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 150154 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037689
ELECTRON MICROSCOPYf_angle_d0.53110449
ELECTRON MICROSCOPYf_dihedral_angle_d4.31064
ELECTRON MICROSCOPYf_chiral_restr0.041175
ELECTRON MICROSCOPYf_plane_restr0.0031335

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