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

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Basic information

Entry
Database: PDB / ID: 9cpf
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
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 / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive 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 / B cell homeostasis / positive regulation of calcium ion transport into cytosol / positive regulation of proteolysis / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / blood vessel remodeling / 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 / response to gamma radiation / regulation of mitochondrial membrane potential / apoptotic signaling pathway / positive regulation of protein-containing complex assembly / response to hydrogen peroxide / establishment of localization in cell / 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 speciessynthetic construct (others)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsAggarwal, 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

Downloads & links

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Assembly

Deposited unit
A: Induced myeloid leukemia cell differentiation protein Mcl-1
B: Induced myeloid leukemia cell differentiation protein Mcl-1
C: Induced myeloid leukemia cell differentiation protein Mcl-1
D: Induced myeloid leukemia cell differentiation protein Mcl-1
E: Bcl-2 homologous antagonist/killer
F: Bcl-2 homologous antagonist/killer
G: Bcl-2 homologous antagonist/killer
H: Bcl-2 homologous antagonist/killer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)240,43212
Polymers239,0638
Non-polymers1,3694
Water36,9132049
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
E: Bcl-2 homologous antagonist/killer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,1083
Polymers59,7662
Non-polymers3421
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2550 Å2
ΔGint-10 kcal/mol
Surface area21760 Å2
MethodPISA
2
B: Induced myeloid leukemia cell differentiation protein Mcl-1
F: Bcl-2 homologous antagonist/killer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,1083
Polymers59,7662
Non-polymers3421
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2570 Å2
ΔGint-8 kcal/mol
Surface area20930 Å2
MethodPISA
3
C: Induced myeloid leukemia cell differentiation protein Mcl-1
G: Bcl-2 homologous antagonist/killer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,1083
Polymers59,7662
Non-polymers3421
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2530 Å2
ΔGint-9 kcal/mol
Surface area21700 Å2
MethodPISA
4
D: Induced myeloid leukemia cell differentiation protein Mcl-1
H: Bcl-2 homologous antagonist/killer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,1083
Polymers59,7662
Non-polymers3421
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2670 Å2
ΔGint-11 kcal/mol
Surface area21500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.757, 110.517, 126.019
Angle α, β, γ (deg.)90.00, 101.17, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 57339.945 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / 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: 2425.704 Da / Num. of mol.: 4
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: Polysaccharide
alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose


Type: oligosaccharide / Mass: 342.297 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2049 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.57 Å3/Da / Density % sol: 52.13 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 15-25% PEG 4000, 0.2 M lithium sulfate, 0.1 M TRIS pH 8.5

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Data collection

DiffractionMean temperature: 124 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 6, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→46.35 Å / Num. obs: 504731 / % possible obs: 97.63 % / Redundancy: 3.3 % / CC1/2: 0.999 / Net I/σ(I): 13.24
Reflection shellResolution: 1.7→1.73 Å / Rmerge(I) obs: 0.599 / Num. unique obs: 19449

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Processing

Software
NameVersionClassification
PHENIX(1.21_5207: ???)refinement
XDSdata reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→46.35 Å / SU ML: 0.34 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 32.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.224 3192 0.63 %
Rwork0.1854 --
obs0.1856 504731 97.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.7→46.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16213 0 92 2049 18354
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01216838
X-RAY DIFFRACTIONf_angle_d1.1822903
X-RAY DIFFRACTIONf_dihedral_angle_d14.4016124
X-RAY DIFFRACTIONf_chiral_restr0.062558
X-RAY DIFFRACTIONf_plane_restr0.0112968
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.730.56741240.513519449X-RAY DIFFRACTION87
1.73-1.750.44551350.483821020X-RAY DIFFRACTION94
1.75-1.780.40861390.448622031X-RAY DIFFRACTION99
1.78-1.810.46281420.413222091X-RAY DIFFRACTION99
1.81-1.840.37321430.376722085X-RAY DIFFRACTION99
1.84-1.880.31251390.354722173X-RAY DIFFRACTION99
1.88-1.920.44151390.370821971X-RAY DIFFRACTION99
1.92-1.960.33511360.307122052X-RAY DIFFRACTION99
1.96-2.010.28091410.253122192X-RAY DIFFRACTION99
2.01-2.060.27481430.240522030X-RAY DIFFRACTION99
2.06-2.110.27961410.230422051X-RAY DIFFRACTION99
2.11-2.170.27661400.216921867X-RAY DIFFRACTION98
2.17-2.240.33311360.216721472X-RAY DIFFRACTION97
2.24-2.320.26421380.214422180X-RAY DIFFRACTION99
2.32-2.420.23381380.168822088X-RAY DIFFRACTION99
2.42-2.530.23441410.171322171X-RAY DIFFRACTION99
2.53-2.660.19761400.166822054X-RAY DIFFRACTION99
2.66-2.830.25581410.168322175X-RAY DIFFRACTION99
2.83-3.050.21421410.165821876X-RAY DIFFRACTION98
3.05-3.350.17291350.157521732X-RAY DIFFRACTION97
3.35-3.840.18741430.1422176X-RAY DIFFRACTION99
3.84-4.830.17041410.125322102X-RAY DIFFRACTION99
4.83-46.350.17251360.167220501X-RAY DIFFRACTION92

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