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- PDB-8svy: MBP-Mcl1 in complex with ligand 10 -

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Basic information

Entry
Database: PDB / ID: 8svy
TitleMBP-Mcl1 in complex with ligand 10
ComponentsMaltose/maltodextrin-binding periplasmic protein, Induced myeloid leukemia cell differentiation protein Mcl-1 chimera
KeywordsSIGNALING PROTEIN / Myeloid cell leukemia 1 / Mcl-1 / B-cell lymphoma 2 / Bcl-2 / BH3 mimetic / Protein-protein interaction / Modulator / Apoptosis / Cancer / Leukemia / Myeloma / Lymphoma
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / mitochondrial fusion / channel activity / Bcl-2 family protein complex / BH3 domain binding / maltose binding / maltose transport / maltodextrin transmembrane transport ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / mitochondrial fusion / channel activity / Bcl-2 family protein complex / BH3 domain binding / maltose binding / maltose transport / maltodextrin transmembrane transport / carbohydrate transmembrane transporter activity / negative regulation of anoikis / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of autophagy / release of cytochrome c from mitochondria / response to cytokine / Signaling by ALK fusions and activated point mutants / intrinsic apoptotic signaling pathway in response to DNA damage / outer membrane-bounded periplasmic space / regulation of apoptotic process / Interleukin-4 and Interleukin-13 signaling / mitochondrial outer membrane / positive regulation of apoptotic process / protein heterodimerization activity / DNA damage response / negative regulation of apoptotic process / protein homodimerization activity / mitochondrion / nucleoplasm / membrane / nucleus / 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 (B-Cell lymphoma); contains BH1, BH2 regions / Bcl-2 family / Bcl-2, Bcl-2 homology region 1-3 ...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 (B-Cell lymphoma); contains BH1, BH2 regions / Bcl-2 family / Bcl-2, Bcl-2 homology region 1-3 / Bcl2-like / 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 / Chem-WUC / Maltose/maltodextrin-binding periplasmic protein / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.47 Å
AuthorsMiller, B.R. / Shaffer, P.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1.
Authors: Demin, S. / Peschiulli, A. / Velter, A.I. / Vos, A. / De Boeck, B. / Miller, B. / Rombouts, F.J.R. / Reuillon, T. / Lento, W. / Blanco, M.D. / Jouffroy, M. / Steyvers, H. / Bekkers, M. / ...Authors: Demin, S. / Peschiulli, A. / Velter, A.I. / Vos, A. / De Boeck, B. / Miller, B. / Rombouts, F.J.R. / Reuillon, T. / Lento, W. / Blanco, M.D. / Jouffroy, M. / Steyvers, H. / Bekkers, M. / Altrocchi, C. / Pietrak, B. / Koo, S.J. / Szewczuk, L. / Attar, R. / Philippar, U.
History
DepositionMay 17, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 9, 2023Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)58,7408
Polymers57,3111
Non-polymers1,4297
Water12,106672
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: fluorescence resonance energy transfer, Tb-MCL-1 HTRF assay
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.040, 137.032, 38.715
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-1145-

HOH

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Components

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein Maltose/maltodextrin-binding periplasmic protein, Induced myeloid leukemia cell differentiation protein Mcl-1 chimera / 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: 57310.883 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: malE, 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: obtained synthetically / 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

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Non-polymers , 4 types, 678 molecules

#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-WUC / (15P)-17-chloro-33-fluoro-12-[(2-methoxyethoxy)methyl]-5,14,22-trimethyl-28-oxa-9-thia-5,6,13,14,22-pentaazaheptacyclo[27.7.1.1~4,7~.0~11,15~.0~16,21~.0~20,24~.0~30,35~]octatriaconta-1(36),4(38),6,11(15),12,16,18,20,23,29(37),30,32,34-tridecaene-23-carboxylic acid


Mass: 746.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H41ClFN5O5S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 672 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.25 Å3/Da / Density % sol: 45.47 %
Crystal growTemperature: 285 K / Method: vapor diffusion / pH: 7.5 / Details: 19% (w/v) PEG3350, 0.17M Mg formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Dec 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.47→37.28 Å / Num. obs: 89536 / % possible obs: 98.4 % / Redundancy: 6.5 % / CC1/2: 0.999 / Rpim(I) all: 0.021 / Rrim(I) all: 0.054 / Rsym value: 0.05 / Net I/σ(I): 16.6
Reflection shellResolution: 1.47→1.49 Å / Mean I/σ(I) obs: 1.4 / Num. unique obs: 4501 / CC1/2: 0.563 / Rpim(I) all: 0.527 / Rrim(I) all: 1.36 / Rsym value: 1.248 / % possible all: 99.5

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Processing

Software
NameVersionClassification
autoPROC1.1.7data reduction
XDS(VERSION Jan 31data reduction
autoPROC(Version 1.1.7)data scaling
Aimlessdata scaling
REFMAC5.8.0267refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.47→37.28 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.963 / SU B: 1.71 / SU ML: 0.057 / Cross valid method: THROUGHOUT / ESU R: 0.071 / ESU R Free: 0.076 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20633 4595 5.1 %RANDOM
Rwork0.16995 ---
obs0.17176 84932 98.32 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.192 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å2-0 Å2-0 Å2
2---0.59 Å20 Å2
3---0.55 Å2
Refinement stepCycle: LAST / Resolution: 1.47→37.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4038 0 97 672 4807
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0134506
X-RAY DIFFRACTIONr_bond_other_d0.0020.0174225
X-RAY DIFFRACTIONr_angle_refined_deg1.4211.6716152
X-RAY DIFFRACTIONr_angle_other_deg1.4781.6019765
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7165581
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.04523.548217
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.17915.093756
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2421520
X-RAY DIFFRACTIONr_chiral_restr0.0740.2586
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025250
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021010
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_it1.0742.0042237
X-RAY DIFFRACTIONr_mcbond_other1.0732.0042236
X-RAY DIFFRACTIONr_mcangle_it1.6563.0022847
X-RAY DIFFRACTIONr_mcangle_other1.6563.0032848
X-RAY DIFFRACTIONr_scbond_it1.5772.2052269
X-RAY DIFFRACTIONr_scbond_other1.5772.2062270
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.4513.2263306
X-RAY DIFFRACTIONr_long_range_B_refined4.725.3465458
X-RAY DIFFRACTIONr_long_range_B_other4.43124.3115287
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.47→1.506 Å
RfactorNum. reflection% reflection
Rfree0.32 312 -
Rwork0.309 6297 -
obs--99.19 %
Refinement TLS params.Method: refined / Origin x: -16.046 Å / Origin y: 54.668 Å / Origin z: -6.651 Å
111213212223313233
T0.0126 Å20.0017 Å20.0012 Å2-0.0165 Å20.0048 Å2--0.0227 Å2
L1.4684 °20.3274 °2-1.0546 °2-2.4898 °20.5206 °2--3.0519 °2
S-0.0811 Å °-0.0128 Å °-0.0227 Å °0.0422 Å °0.0041 Å °-0.0146 Å °0.1886 Å °0.0508 Å °0.0771 Å °

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