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

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Basic information

Entry
Database: PDB / ID: 9cpe
TitleStructural basis of BAK sequestration by MCL-1 and consequences for apoptosis initiation
ComponentsBcl-2 homologous antagonist/killer
KeywordsAPOPTOSIS / Anti-apoptosis / Mitochondrial poration / BCL-2 family / Cell fate
Function / homology
Function and homology information


Activation and oligomerization of BAK protein / BH domain binding / B cell negative selection / BAK complex / negative regulation of endoplasmic reticulum calcium ion concentration / response to fungus / response to mycotoxin / limb morphogenesis / Release of apoptotic factors from the mitochondria / apoptotic process involved in blood vessel morphogenesis ...Activation and oligomerization of BAK protein / BH domain binding / B cell negative selection / BAK complex / negative regulation of endoplasmic reticulum calcium ion concentration / response to fungus / response to mycotoxin / limb morphogenesis / Release of apoptotic factors from the mitochondria / apoptotic process involved in blood vessel morphogenesis / post-embryonic camera-type eye morphogenesis / endocrine pancreas development / establishment or maintenance of transmembrane electrochemical gradient / B cell apoptotic process / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / 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 / fibroblast apoptotic process / response to UV-C / mitochondrial fusion / Bcl-2 family protein complex / myeloid cell homeostasis / porin activity / thymocyte apoptotic process / 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 / positive regulation of calcium ion transport into cytosol / B cell homeostasis / positive regulation of proteolysis / blood vessel remodeling / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / animal organ regeneration / cellular response to unfolded protein / Pyroptosis / heat shock protein binding / extrinsic apoptotic signaling pathway in absence of ligand / intrinsic apoptotic signaling pathway / release of cytochrome c from mitochondria / epithelial cell proliferation / regulation of mitochondrial membrane potential / response to gamma radiation / positive regulation of protein-containing complex assembly / apoptotic signaling pathway / establishment of localization in cell / 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 / transmembrane transporter binding / mitochondrial outer membrane / regulation of cell cycle / positive regulation of apoptotic process / response to xenobiotic stimulus / protein heterodimerization activity / 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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.49 Å
AuthorsOjoawo, A. / Jayaraman, S. / 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

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Assembly

Deposited unit
A: Bcl-2 homologous antagonist/killer


Theoretical massNumber of molelcules
Total (without water)18,8241
Polymers18,8241
Non-polymers00
Water2,900161
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)73.319, 73.319, 45.202
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

#1: Protein Bcl-2 homologous antagonist/killer / Apoptosis regulator BAK / Bcl-2-like protein 7 / Bcl2-L-7


Mass: 18824.066 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
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 161 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 1.98 Å3/Da / Density % sol: 37.88 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 15-25% PEG 3350, 0.1 M sodium acetate, 0.1M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 124 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X17B1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 2, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 1.48→28.47 Å / Num. obs: 22525 / % possible obs: 97.97 % / Redundancy: 8.1 % / CC1/2: 0.982 / Net I/σ(I): 11.6
Reflection shellResolution: 2.36→2.97 Å / Rmerge(I) obs: 0.369 / Num. unique obs: 2759

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Processing

Software
NameVersionClassification
PHENIX(1.21_5207: ???)refinement
XDSdata reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.49→28.47 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 23.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.212 1147 5.09 %
Rwork0.1646 --
obs0.167 22525 97.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.49→28.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1250 0 0 161 1411
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.011281
X-RAY DIFFRACTIONf_angle_d1.0471736
X-RAY DIFFRACTIONf_dihedral_angle_d15.536454
X-RAY DIFFRACTIONf_chiral_restr0.067185
X-RAY DIFFRACTIONf_plane_restr0.009226
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.49-1.550.36341020.33152327X-RAY DIFFRACTION85
1.55-1.630.2491540.19782655X-RAY DIFFRACTION99
1.63-1.740.24231700.18662685X-RAY DIFFRACTION100
1.74-1.870.2151630.15172712X-RAY DIFFRACTION100
1.87-2.060.24111270.15312729X-RAY DIFFRACTION100
2.06-2.360.18741390.13862731X-RAY DIFFRACTION100
2.36-2.970.17221310.14572759X-RAY DIFFRACTION100
2.97-28.470.19091610.15632780X-RAY DIFFRACTION100

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