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- PDB-6qfq: Structure of human Mcl-1 in complex with indole acid inhibitor -

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Basic information

Entry
Database: PDB / ID: 6qfq
TitleStructure of human Mcl-1 in complex with indole acid inhibitor
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / MCL1 / BCL2 / 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 / response to cytokine ...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 / response to cytokine / extrinsic apoptotic signaling pathway in absence of ligand / 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 / 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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-J3E / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsDokurno, P. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Graham, C.J. / Harris, R. / Jordan, A.M. / Matassova, N. / Pedder, C. ...Dokurno, P. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Graham, C.J. / Harris, R. / Jordan, A.M. / Matassova, N. / Pedder, C. / Ray, S. / Roughley, S. / Smith, J. / Walmsley, C. / Wang, Y. / Whitehead, N. / Williamson, D.S. / Casara, P. / Le Diguarher, T. / Hickman, J. / Stark, J. / Kotschy, A. / Geneste, O. / Hubbard, R.E.
CitationJournal: Acs Omega / Year: 2019
Title: Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1.
Authors: Murray, J.B. / Davidson, J. / Chen, I. / Davis, B. / Dokurno, P. / Graham, C.J. / Harris, R. / Jordan, A. / Matassova, N. / Pedder, C. / Ray, S. / Roughley, S.D. / Smith, J. / Walmsley, C. / ...Authors: Murray, J.B. / Davidson, J. / Chen, I. / Davis, B. / Dokurno, P. / Graham, C.J. / Harris, R. / Jordan, A. / Matassova, N. / Pedder, C. / Ray, S. / Roughley, S.D. / Smith, J. / Walmsley, C. / Wang, Y. / Whitehead, N. / Williamson, D.S. / Casara, P. / Le Diguarher, T. / Hickman, J. / Stark, J. / Kotschy, A. / Geneste, O. / Hubbard, R.E.
History
DepositionJan 10, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 12, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 11, 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.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
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)20,3723
Polymers19,4931
Non-polymers8792
Water1,40578
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.064, 48.064, 148.470
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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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-J3E / 7-(3,5-dimethyl-1~{H}-pyrazol-4-yl)-3-(3-naphthalen-1-yloxypropyl)-1~{H}-indole-2-carboxylic acid


Mass: 439.506 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H25N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 78 / 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: 2.2 Å3/Da / Density % sol: 44.08 %
Crystal growTemperature: 292 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: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 15, 2009
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.6→50 Å / Num. obs: 43693 / % possible obs: 99 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.078 / Χ2: 1.025 / Net I/σ(I): 10.2 / Num. measured all: 199340
Reflection shell
Resolution (Å)Redundancy (%)Num. unique obsΧ2Diffraction-ID% possible allRmerge(I) obs
1.6-1.664.243600.967198.8
1.66-1.724.543530.963199.50.689
1.72-1.84.643730.985199.50.491
1.8-1.94.544040.986199.60.331
1.9-2.024.543961.043199.80.194
2.02-2.174.644071.083199.80.125
2.17-2.394.743851.076199.60.091
2.39-2.744.743751.026199.30.095
2.74-3.454.744121.08199.20.077

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.5.0066refinement
PDB_EXTRACT3.24data extraction
DENZOdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2nl9

2nl9


Resolution: 1.6→45.73 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.936 / SU B: 2.079 / SU ML: 0.073 / SU R Cruickshank DPI: 0.0895 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.098 / ESU R Free: 0.102
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2548 1214 5.1 %RANDOM
Rwork0.2141 ---
obs0.2161 22512 99.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 68.4 Å2 / Biso mean: 26.082 Å2 / Biso min: 11.04 Å2
Baniso -1Baniso -2Baniso -3
1-0.32 Å20 Å20 Å2
2--0.32 Å20 Å2
3----0.65 Å2
Refinement stepCycle: final / Resolution: 1.6→45.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1208 0 66 78 1352
Biso mean--21.88 36.12 -
Num. residues----150
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0270.0211305
X-RAY DIFFRACTIONr_angle_refined_deg2.2712.0051763
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5125151
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.93522.66760
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.37115231
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.051514
X-RAY DIFFRACTIONr_chiral_restr0.1580.2185
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.02987
LS refinement shellResolution: 1.601→1.643 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.357 89 -
Rwork0.3 1609 -
all-1698 -
obs--99.71 %

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