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- PDB-6qz6: Structure of Mcl-1 in complex with compound 8b -

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Basic information

Entry
Database: PDB / ID: 6qz6
TitleStructure of Mcl-1 in complex with compound 8b
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / Apoptosis-inhibitor complex / Mcl1 / 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 / BH3 domain binding / negative regulation of anoikis / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / extrinsic apoptotic signaling pathway in absence of ligand ...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 / extrinsic apoptotic signaling pathway in absence of ligand / response to cytokine / negative regulation of autophagy / release of cytochrome c from mitochondria / intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of neuron apoptotic process / Signaling by ALK fusions and activated point mutants / 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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-JLE / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsDokurno, P. / Szlavik, Z. / Ondi, L. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Radics, G. / Murray, J. / Davidson, J. / Chen, I. ...Dokurno, P. / Szlavik, Z. / Ondi, L. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Radics, G. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Hubbard, R.E. / Pedder, C. / Surgenor, A.E. / Smith, J. / Robertson, A. / LeToumelin-Braizat, G. / Cauquil, N. / Zarka, M. / Demarles, D. / Perron-Sierra, F. / Geneste, O. / Kotschy, A.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity.
Authors: Szlavik, Z. / Ondi, L. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Radics, G. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Hubbard, R.E. / Pedder, C. / Dokurno, P. / Surgenor, A. / ...Authors: Szlavik, Z. / Ondi, L. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Radics, G. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Hubbard, R.E. / Pedder, C. / Dokurno, P. / Surgenor, A. / Smith, J. / Robertson, A. / LeToumelin-Braizat, G. / Cauquil, N. / Zarka, M. / Demarles, D. / Perron-Sierra, F. / Claperon, A. / Colland, F. / Geneste, O. / Kotschy, A.
History
DepositionMar 11, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 7, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2019Group: Data collection / 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 1.2Sep 18, 2019Group: Data collection / Refinement description / Category: software / Item: _software.version
Revision 1.3Jan 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

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Assembly

Deposited unit
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9362
Polymers19,4931
Non-polymers4431
Water1,63991
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7900 Å2
Unit cell
Length a, b, c (Å)40.567, 40.567, 331.776
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-585-

HOH

21A-586-

HOH

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Components

#1: Protein Induced myeloid leukemia cell differentiation protein Mcl-1 / Bcl-2-like protein 3 / Bcl2-L-3 / Bcl-2-related protein EAT/mcl1 / mcl1/EAT


Mass: 19493.154 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pLysS / References: UniProt: Q07820
#2: Chemical ChemComp-JLE / (2~{R})-2-[[6-ethyl-5-(1~{H}-indol-4-yl)thieno[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid


Mass: 442.533 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H22N4O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 91 / Source method: isolated from a natural source / Formula: H2O

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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: 2.02 Å3/Da / Density % sol: 39.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.05M BIS-TRIS pH 6.5, 30% v/v Pentaerythritol ethoxylate (15/4 EO/OH), 0.05M Ammonium Sulphate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9762 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 10, 2009
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.8→25 Å / Num. obs: 15065 / % possible obs: 91.2 % / Redundancy: 6.2 % / Rmerge(I) obs: 0.096 / Net I/σ(I): 16.3
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.767 / Mean I/σ(I) obs: 1.1 / % possible all: 61.9

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Processing

Software
NameVersionClassification
DENZOdata reduction
REFMAC5.8.0238refinement
PDB_EXTRACT3.24data extraction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6qfq

6qfq


Resolution: 1.9→20 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.924 / SU B: 3.942 / SU ML: 0.112 / SU R Cruickshank DPI: 0.1832 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.183 / ESU R Free: 0.162
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.254 681 5.1 %RANDOM
Rwork0.2195 ---
obs0.2212 12647 95.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 109.18 Å2 / Biso mean: 38.096 Å2 / Biso min: 20.65 Å2
Baniso -1Baniso -2Baniso -3
1-0.43 Å20.21 Å20 Å2
2--0.43 Å2-0 Å2
3----1.39 Å2
Refinement stepCycle: final / Resolution: 1.9→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1197 0 32 91 1320
Biso mean--29.31 48.84 -
Num. residues----151
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0131258
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171173
X-RAY DIFFRACTIONr_angle_refined_deg1.671.6791700
X-RAY DIFFRACTIONr_angle_other_deg1.4311.62677
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.715152
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.94920.85770
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.99515222
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.5491512
X-RAY DIFFRACTIONr_chiral_restr0.0870.2160
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021414
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02280
LS refinement shellResolution: 1.9→2.002 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.272 94 -
Rwork0.274 1734 -
all-1828 -
obs--94.32 %

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