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- PDB-8zcs: Crystal structure of the MBP-MCL1 complex with highly selective a... -

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Basic information

Entry
Database: PDB / ID: 8zcs
TitleCrystal structure of the MBP-MCL1 complex with highly selective and potent Cyclic peptide inhibitor
Components
  • Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
  • TYR-LEU-LEU-PHE-TRP-ARG-ASP-GLU-LEU-ILE-LEU-LEU-CCJ-NH2
KeywordsAPOPTOSIS / Inhibitor / molecular glue / cyclic peptide
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 / detection of maltose stimulus / maltose transport complex / carbohydrate transport / BH3 domain binding / negative regulation of anoikis ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / detection of maltose stimulus / maltose transport complex / carbohydrate transport / 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 / ATP-binding cassette (ABC) transporter complex / release of cytochrome c from mitochondria / cell chemotaxis / 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 / periplasmic space / 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-maltotetraose / alpha-maltopentaose / Maltose/maltodextrin-binding periplasmic protein / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesEscherichia coli K-12 (bacteria)
Homo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.79 Å
AuthorsLi, F.W.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2025
Title: De novo discovery of a molecular glue-like macrocyclic peptide that induces MCL1 homodimerization.
Authors: Li, F. / Zhang, M. / Liu, C. / Cheng, J. / Yang, Y. / Peng, X. / Li, Z. / Cai, W. / Yu, H. / Wu, J. / Guo, Y. / Geng, H. / Fa, Y. / Zhang, Y. / Wu, D. / Yin, Y.
History
DepositionApr 30, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 19, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 2, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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
B: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
C: TYR-LEU-LEU-PHE-TRP-ARG-ASP-GLU-LEU-ILE-LEU-LEU-CCJ-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,5385
Polymers117,0433
Non-polymers1,4952
Water2,900161
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3320 Å2
ΔGint-20 kcal/mol
Surface area40350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.854, 75.709, 121.222
Angle α, β, γ (deg.)90.00, 95.77, 90.00
Int Tables number4
Space group name H-MP1211

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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: 57644.223 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli K-12 (bacteria), (gene. exp.) Homo sapiens (human)
Gene: malE, b4034, JW3994, MCL1, BCL2L3 / Production host: Escherichia coli (E. coli) / References: UniProt: P0AEX9, UniProt: Q07820
#2: Protein/peptide TYR-LEU-LEU-PHE-TRP-ARG-ASP-GLU-LEU-ILE-LEU-LEU-CCJ-NH2


Mass: 1754.101 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose


Type: oligosaccharide, Oligosaccharide / Class: Substrate analog / Mass: 666.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: oligosaccharide / References: alpha-maltotetraose
DescriptorTypeProgram
DGlcpa1-4DGlcpa1-4DGlcpa1-4DGlcpa1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,4,3/[a2122h-1a_1-5]/1-1-1-1/a4-b1_b4-c1_c4-d1WURCSPDB2Glycan 1.1.0
[][a-D-Glcp]{[(4+1)][a-D-Glcp]{[(4+1)][a-D-Glcp]{[(4+1)][a-D-Glcp]{}}}}LINUCSPDB-CARE
#4: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D- ...alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose


Type: oligosaccharide, Oligosaccharide / Class: Substrate analog / Mass: 828.719 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: oligosaccharide / References: alpha-maltopentaose
DescriptorTypeProgram
DGlcpa1-4DGlcpa1-4DGlcpa1-4DGlcpa1-4DGlcpa1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,5,4/[a2122h-1a_1-5]/1-1-1-1-1/a4-b1_b4-c1_c4-d1_d4-e1WURCSPDB2Glycan 1.1.0
[][a-D-Glcp]{[(4+1)][a-D-Glcp]{[(4+1)][a-D-Glcp]{[(4+1)][a-D-Glcp]{[(4+1)][a-D-Glcp]{}}}}}LINUCSPDB-CARE
#5: Water ChemComp-HOH / water


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

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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: 2.27 Å3/Da / Density % sol: 45.73 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop
Details: 0.2 M MgCl2, 0.1 Tris pH 8.5, 25% w/v Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NFPSS / Beamline: BL19U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 23, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.79→50 Å / Num. obs: 24254 / % possible obs: 93.3 % / Redundancy: 4.3 % / CC1/2: 0.979 / CC star: 0.995 / Rmerge(I) obs: 0.179 / Rpim(I) all: 0.094 / Rrim(I) all: 0.204 / Χ2: 1.007 / Net I/σ(I): 6.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.8-2.853.60.60110530.5020.8180.3440.6970.95982.8
2.85-2.93.60.61610820.5550.8450.3580.7180.96882.6
2.9-2.963.70.64510340.6670.8950.3680.7480.95382.9
2.96-3.0240.61211270.6870.9020.340.7060.95785.9
3.02-3.084.10.60711220.730.9190.3290.6951.06285.8
3.08-3.154.10.52811080.8110.9460.2820.6020.9487.6
3.15-3.234.10.48911490.8270.9510.2630.5591.00889.1
3.23-3.324.10.43211900.8370.9550.2390.4971.04290.6
3.32-3.4240.42411950.8290.9520.2360.4881.00993.1
3.42-3.534.30.37612350.8390.9550.2020.431.1196
3.53-3.654.40.30512680.9230.980.1610.3471.04896.4
3.65-3.84.30.27812620.9370.9840.1490.3171.1197.4
3.8-3.974.70.23212790.9540.9880.1210.2631.08598.8
3.97-4.184.60.19112910.9710.9920.0990.2161.07499.2
4.18-4.444.60.17312920.9770.9940.090.1951.08499.6
4.44-4.794.50.14413120.9860.9960.0750.1631.05899.8
4.79-5.274.60.14512970.9810.9950.0740.1641.03199.9
5.27-6.035.10.15312960.9830.9960.0750.1710.94499.9
6.03-7.594.90.11513210.9870.9970.0570.1290.999.4
7.59-504.90.0613410.9950.9990.0290.0670.79798.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.79→47.21 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.845 / SU B: 21.076 / SU ML: 0.408 / Cross valid method: THROUGHOUT / ESU R Free: 0.573 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29554 1036 4.9 %RANDOM
Rwork0.2045 ---
obs0.20887 20113 80.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 47.449 Å2
Baniso -1Baniso -2Baniso -3
1--0.85 Å20 Å2-1.11 Å2
2---2.09 Å20 Å2
3---3.1 Å2
Refinement stepCycle: 1 / Resolution: 2.79→47.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7870 0 111 161 8142
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0138172
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177650
X-RAY DIFFRACTIONr_angle_refined_deg1.4491.65811105
X-RAY DIFFRACTIONr_angle_other_deg1.1821.59717625
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.11551009
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.36823.416401
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.052151315
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.191537
X-RAY DIFFRACTIONr_chiral_restr0.060.21103
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.029184
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021828
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.3085.0094055
X-RAY DIFFRACTIONr_mcbond_other3.3085.0094054
X-RAY DIFFRACTIONr_mcangle_it5.3287.5035054
X-RAY DIFFRACTIONr_mcangle_other5.3287.5035055
X-RAY DIFFRACTIONr_scbond_it3.1965.2164117
X-RAY DIFFRACTIONr_scbond_other3.1945.2164117
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.2727.6976051
X-RAY DIFFRACTIONr_long_range_B_refined10.76794.83934589
X-RAY DIFFRACTIONr_long_range_B_other10.76694.87634552
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 15396 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.12 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.79→2.859 Å
RfactorNum. reflection% reflection
Rfree0.356 50 -
Rwork0.271 939 -
obs--51.78 %

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