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- PDB-8y20: Crystal structure of the Mcl-1 in complex with A-1210477 -

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Basic information

Entry
Database: PDB / ID: 8y20
TitleCrystal structure of the Mcl-1 in complex with A-1210477
ComponentsMaltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / MCL-1 / BAK / BH3
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / carbohydrate transmembrane transporter activity ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / extrinsic apoptotic signaling pathway in absence of ligand / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / response to cytokine / negative regulation of autophagy / release of cytochrome c from mitochondria / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / positive regulation of neuron apoptotic process / outer membrane-bounded periplasmic space / channel activity / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / mitochondrial outer membrane / positive regulation of apoptotic process / protein heterodimerization activity / DNA damage response / negative regulation of apoptotic process / mitochondrion / nucleoplasm / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
Apoptosis regulator, Mcl-1 / 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 ...Apoptosis regulator, Mcl-1 / 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 / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein
Similarity search - Domain/homology
alpha-maltose / : / Maltose/maltodextrin-binding periplasmic protein / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesEscherichia coli O157:H7 (bacteria)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.23 Å
AuthorsWang, H. / Guo, M. / Wei, H. / Chen, Y.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31900880 China
National Natural Science Foundation of China (NSFC)82273496 China
National Natural Science Foundation of China (NSFC)819740748 China
Citation
Journal: Cell Death Differ. / Year: 2025
Title: Deciphering molecular specificity in MCL-1/BAK interaction and its implications for designing potent MCL-1 inhibitors.
Authors: Wei, H. / Wang, H. / Xiang, S. / Wang, J. / Qu, L. / Chen, X. / Guo, M. / Lu, X. / Chen, Y.
#1: Journal: Res Sq / Year: 2024
Title: Deciphering Molecular Specificity in MCL-1/BAK Interaction and Its Implications for Designing Potent MCL-1 Inhibitors
Authors: Chen, Y. / Wei, H. / Wang, H. / Xiang, S. / Wang, J. / Qu, L. / Chen, X. / Guo, M. / Lu, X.
History
DepositionJan 25, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 19, 2025Group: Database references / Category: citation / citation_author

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,4183
Polymers57,2261
Non-polymers1,1922
Water2,558142
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area810 Å2
ΔGint8 kcal/mol
Surface area21590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.100, 137.280, 38.660
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1 / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Bcl-2-like protein 3 / Bcl2-L- ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Bcl-2-like protein 3 / Bcl2-L-3 / Bcl-2-related protein EAT/mcl1 / mcl1/EAT


Mass: 57225.867 Da / Num. of mol.: 1 / Mutation: E173A,N174A,K240A,K391A,K394A,R398A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli O157:H7 (bacteria), (gene. exp.) Homo sapiens (human)
Gene: malE, Z5632, ECs5017, MCL1, BCL2L3 / Production host: Escherichia coli (E. coli) / References: UniProt: P0AEY0, UniProt: Q07820
#2: 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
#3: Chemical ChemComp-A1LXV / A-1210477 / 1668553-26-1


Mass: 850.037 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C46H55N7O7S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 142 / 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: 2.32 Å3/Da / Density % sol: 47 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 25% PEG 3350, 0.2M Magnesium Formate, 1mM Maltose

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97923 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 24, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97923 Å / Relative weight: 1
ReflectionResolution: 2.23→38.66 Å / Num. obs: 27170 / % possible obs: 99.78 % / Redundancy: 12.7 % / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.1189 / Rpim(I) all: 0.03452 / Rrim(I) all: 0.1239 / Net I/σ(I): 16.6
Reflection shellResolution: 2.23→2.31 Å / Redundancy: 13.3 % / Rmerge(I) obs: 1.289 / Mean I/σ(I) obs: 2.32 / Num. unique obs: 2601 / CC1/2: 0.89 / CC star: 0.971 / Rpim(I) all: 0.3645 / Rrim(I) all: 1.341 / % possible all: 99.42

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Processing

Software
NameVersionClassification
PHENIX(1.15.2_3472: ???)refinement
XDSdata reduction
xia2data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.23→38.66 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2431 1997 7.35 %
Rwork0.1871 --
obs0.1912 27170 99.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.23→38.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3952 0 84 142 4178
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0134136
X-RAY DIFFRACTIONf_angle_d0.8845627
X-RAY DIFFRACTIONf_dihedral_angle_d9.1862437
X-RAY DIFFRACTIONf_chiral_restr0.066620
X-RAY DIFFRACTIONf_plane_restr0.006721
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.23-2.27550.30561410.2651784X-RAY DIFFRACTION99
2.2755-2.3370.27441370.24421731X-RAY DIFFRACTION99
2.337-2.40580.33211400.23811760X-RAY DIFFRACTION100
2.4058-2.48340.27441380.2351751X-RAY DIFFRACTION100
2.4834-2.57220.28761430.22631798X-RAY DIFFRACTION100
2.5722-2.67520.30131390.2131753X-RAY DIFFRACTION100
2.6752-2.79690.28891430.2121794X-RAY DIFFRACTION100
2.7969-2.94430.27531410.21711784X-RAY DIFFRACTION100
2.9443-3.12870.30881420.23021782X-RAY DIFFRACTION100
3.1287-3.37010.27771420.20391791X-RAY DIFFRACTION100
3.3701-3.7090.22631440.18351816X-RAY DIFFRACTION100
3.709-4.24510.21971450.16061832X-RAY DIFFRACTION100
4.2451-5.34620.18131470.14311843X-RAY DIFFRACTION100
5.3462-38.660.20821550.16121954X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.2059-0.87170.33671.23330.18650.7009-0.0573-0.1434-0.08110.03750.1115-0.02940.00840.0985-0.04720.40140.02760.0240.28010.00380.2515-10.766848.803416.5846
21.3819-0.69320.23595.97010.42193.3601-0.02760.11090.016-0.41930.0254-0.0473-0.19140.1962-0.01450.2325-0.0384-0.0080.2617-0.00370.3108-17.51114.8096.7727
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -195 through 160 )
2X-RAY DIFFRACTION2chain 'A' and (resid 161 through 321 )

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