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- PDB-6ybj: Structure of MBP-Mcl-1 in complex with compound 3e -

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Basic information

Entry
Database: PDB / ID: 6ybj
TitleStructure of MBP-Mcl-1 in complex with compound 3e
ComponentsMaltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / Apoptosis-inhibitor complex / Mcl-1 / S64315 / MBP / small molecule inhibitor
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 / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / response to cytokine / extrinsic apoptotic signaling pathway in absence of ligand / ATP-binding cassette (ABC) transporter complex / negative regulation of autophagy / 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 / cytoplasm / cytosol
Similarity search - Function
Apoptosis regulator, Mcl-1 / Blc2-like / Apoptosis Regulator Bcl-x / 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 ...Apoptosis regulator, Mcl-1 / Blc2-like / Apoptosis Regulator Bcl-x / 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 / Periplasmic binding protein-like II / D-Maltodextrin-Binding Protein; domain 2 / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
alpha-maltose / Chem-OJW / Maltose/maltodextrin-binding periplasmic protein / 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 / molecular replacement / Resolution: 2.5 Å
AuthorsDokurno, P. / Surgenor, A.E. / Murray, J.B.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor.
Authors: Szlavik, Z. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Sipos, S. / Radics, G. / Proszenyak, A. / Balint, B. / Murray, J. / Davidson, J. / Chen, I. / Dokurno, P. / Surgenor, A.E. / Daniels, Z. ...Authors: Szlavik, Z. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Sipos, S. / Radics, G. / Proszenyak, A. / Balint, B. / Murray, J. / Davidson, J. / Chen, I. / Dokurno, P. / Surgenor, A.E. / Daniels, Z.M. / Hubbard, R.E. / Le Toumelin-Braizat, G. / Claperon, A. / Lysiak-Auvity, G. / Girard, A.M. / Bruno, A. / Chanrion, M. / Colland, F. / Maragno, A.L. / Demarles, D. / Geneste, O. / Kotschy, A.
History
DepositionMar 17, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 2, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)58,3654
Polymers57,2261
Non-polymers1,1393
Water4,125229
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area770 Å2
ΔGint-7 kcal/mol
Surface area21620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.930, 136.710, 38.340
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: K194A,K197A,R201A
Source method: isolated from a genetically manipulated source
Details: Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820) ...Details: Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820)
Source: (gene. exp.) Escherichia coli O157:H7 (bacteria), (gene. exp.) Homo sapiens (human)
Gene: malE, Z5632, ECs5017, MCL1, BCL2L3 / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): pLysS
References: UniProt: P0AEY0, UniProt: Q07820, UniProt: P0AEX9*PLUS
#2: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose / alpha-maltose


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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-OJW / (2~{R})-2-[5-[3-chloranyl-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(5-fluoranylfuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[(2-methylpyrazol-3-yl)methoxy]phenyl]propanoic acid


Mass: 761.261 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H38ClFN6O6S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 229 / Source method: isolated from a natural source / Formula: H2O
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: 2.2 Å3/Da / Density % sol: 43 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 0.1M BisTris buffer pH 6.5, 20% PegMME5K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.34→46.9 Å / Num. obs: 23098 / % possible obs: 99.7 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.177 / Net I/σ(I): 6.3
Reflection shellResolution: 2.34→2.4 Å / Redundancy: 6.7 % / Rmerge(I) obs: 1.56 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1663 / Rpim(I) all: 0.632 / % possible all: 97.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0258refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5lof

5lof


Resolution: 2.5→20 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.93 / WRfactor Rfree: 0.2494 / WRfactor Rwork: 0.1915 / FOM work R set: 0.7991 / SU B: 11.491 / SU ML: 0.236 / SU R Cruickshank DPI: 1.0855 / SU Rfree: 0.2955 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.086 / ESU R Free: 0.296 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2372 946 5 %RANDOM
Rwork0.1792 ---
obs0.1821 17956 99.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 158.56 Å2 / Biso mean: 50.851 Å2 / Biso min: 25.72 Å2
Baniso -1Baniso -2Baniso -3
1-2.11 Å20 Å2-0 Å2
2---3.81 Å20 Å2
3---1.7 Å2
Refinement stepCycle: final / Resolution: 2.5→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3987 0 77 229 4293
Biso mean--62.5 47.36 -
Num. residues----514
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134166
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173837
X-RAY DIFFRACTIONr_angle_refined_deg1.5281.655661
X-RAY DIFFRACTIONr_angle_other_deg1.2671.5848912
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2975514
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.22823.75200
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.19715682
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.7311517
X-RAY DIFFRACTIONr_chiral_restr0.0660.2548
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024647
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02844
LS refinement shellResolution: 2.5→2.633 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.462 134 -
Rwork0.395 2544 -
all-2678 -
obs--99.93 %

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