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

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Basic information

Entry
Database: PDB / ID: 9cpn
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 / 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 speciessynthetic construct (others)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 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)240,31212
Polymers238,9428
Non-polymers1,3694
Water21,3481185
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)60,0783
Polymers59,7362
Non-polymers3421
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2700 Å2
ΔGint-10 kcal/mol
Surface area22210 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)60,0783
Polymers59,7362
Non-polymers3421
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2640 Å2
ΔGint-10 kcal/mol
Surface area21460 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)60,0783
Polymers59,7362
Non-polymers3421
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2730 Å2
ΔGint-8 kcal/mol
Surface area21500 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)60,0783
Polymers59,7362
Non-polymers3421
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2530 Å2
ΔGint-9 kcal/mol
Surface area21190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.614, 109.330, 125.127
Angle α, β, γ (deg.)90.00, 100.68, 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: 57281.844 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: 2453.757 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, Oligosaccharide / Class: Nutrient / Mass: 342.297 Da / Num. of mol.: 4
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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1185 / 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: 2.5 Å3/Da / Density % sol: 50.83 %
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: 1.89→34.69 Å / Num. obs: 182985 / % possible obs: 98.29 % / Redundancy: 3.8 % / CC1/2: 0.98 / Net I/σ(I): 12
Reflection shellResolution: 1.89→1.92 Å / Rmerge(I) obs: 0.3931 / Num. unique obs: 5218

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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: 1.89→34.69 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 2.02 / Phase error: 28.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2435 9115 4.98 %
Rwork0.1911 --
obs0.1937 182862 98.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.89→34.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16426 0 92 1185 17703
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01317005
X-RAY DIFFRACTIONf_angle_d1.34823107
X-RAY DIFFRACTIONf_dihedral_angle_d15.8656173
X-RAY DIFFRACTIONf_chiral_restr0.1422583
X-RAY DIFFRACTIONf_plane_restr0.0122992
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.89-1.920.41512870.39315218X-RAY DIFFRACTION90
1.92-1.940.4073180.37675744X-RAY DIFFRACTION98
1.94-1.960.39093010.35555784X-RAY DIFFRACTION98
1.96-1.990.37942740.33725793X-RAY DIFFRACTION98
1.99-2.010.36683060.32245744X-RAY DIFFRACTION98
2.01-2.040.34542910.31055673X-RAY DIFFRACTION97
2.04-2.070.33992910.29175603X-RAY DIFFRACTION95
2.07-2.10.31213020.28365585X-RAY DIFFRACTION95
2.1-2.130.33163130.25955833X-RAY DIFFRACTION100
2.13-2.170.30953080.24445898X-RAY DIFFRACTION100
2.17-2.210.28293040.22385843X-RAY DIFFRACTION100
2.21-2.250.27933030.21615881X-RAY DIFFRACTION100
2.25-2.290.28042990.20475865X-RAY DIFFRACTION100
2.29-2.340.26383150.18875878X-RAY DIFFRACTION100
2.34-2.390.2373260.1745822X-RAY DIFFRACTION100
2.39-2.440.24433000.18155846X-RAY DIFFRACTION99
2.44-2.50.23633140.18375843X-RAY DIFFRACTION99
2.5-2.570.25352930.17675879X-RAY DIFFRACTION100
2.57-2.650.2552780.17995883X-RAY DIFFRACTION99
2.65-2.730.25753260.17515819X-RAY DIFFRACTION99
2.73-2.830.24152980.16655750X-RAY DIFFRACTION98
2.83-2.940.23922880.17475685X-RAY DIFFRACTION96
2.94-3.080.24872910.18375696X-RAY DIFFRACTION97
3.08-3.240.24353500.17995846X-RAY DIFFRACTION100
3.24-3.440.23693030.16825900X-RAY DIFFRACTION100
3.44-3.710.20783250.15675895X-RAY DIFFRACTION100
3.71-4.080.18782790.13615911X-RAY DIFFRACTION100
4.08-4.670.16123150.1195912X-RAY DIFFRACTION99
4.67-5.870.16033280.14065747X-RAY DIFFRACTION97
5.88-34.690.22112890.18835971X-RAY DIFFRACTION98

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