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- PDB-6qyp: Structure of Mcl-1 in complex with compound 13 -

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Basic information

Entry
Database: PDB / ID: 6qyp
TitleStructure of Mcl-1 in complex with compound 13
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 / cellular homeostasis / cell fate determination / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of autophagy / release of cytochrome c from mitochondria / response to cytokine / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / 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 / 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 (B-Cell lymphoma); contains BH1, BH2 regions ...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 (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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-JL5 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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 9, 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)20,0602
Polymers19,4931
Non-polymers5671
Water50428
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)40.165, 40.165, 327.800
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-526-

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-JL5 / (2~{R})-2-[5-[3-chloranyl-2-methyl-5-(4-methylpiperazin-1-yl)-4-oxidanyl-phenyl]-6-ethyl-thieno[2,3-d]pyrimidin-4-yl]oxy-3-phenyl-propanoic acid


Mass: 567.099 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H31ClN4O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 1.96 Å3/Da / Density % sol: 37.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.05M BIS-TRIS pH 6.5; 30% 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: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jan 30, 2012
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.1→29.3 Å / Num. obs: 10131 / % possible obs: 98.9 % / Redundancy: 9.2 % / Rmerge(I) obs: 0.083 / Net I/σ(I): 12.8
Reflection shellResolution: 2.1→2.15 Å / Redundancy: 6.1 % / Rmerge(I) obs: 1.43 / Mean I/σ(I) obs: 0.9 / % possible all: 85.9

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Processing

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

6qfq


Resolution: 2.2→20 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.949 / SU B: 7.647 / SU ML: 0.181 / SU R Cruickshank DPI: 0.2734 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.27 / ESU R Free: 0.22
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2533 482 5.4 %RANDOM
Rwork0.1976 ---
obs0.2006 8454 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 131.69 Å2 / Biso mean: 59.847 Å2 / Biso min: 40.15 Å2
Baniso -1Baniso -2Baniso -3
1-1.64 Å20.82 Å20 Å2
2--1.64 Å20 Å2
3----5.32 Å2
Refinement stepCycle: final / Resolution: 2.2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1197 0 39 28 1264
Biso mean--56.18 64.83 -
Num. residues----151
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0131260
X-RAY DIFFRACTIONr_bond_other_d0.0010.0181166
X-RAY DIFFRACTIONr_angle_refined_deg1.51.6811703
X-RAY DIFFRACTIONr_angle_other_deg1.3561.6032648
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0195150
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.02920.98671
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.06915219
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.2121512
X-RAY DIFFRACTIONr_chiral_restr0.0740.2159
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021413
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02277
LS refinement shellResolution: 2.2→2.317 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.303 58 -
Rwork0.312 1171 -
all-1229 -
obs--100 %

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