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- PDB-3wiy: Crystal structure of Mcl-1 in complex with compound 10 -

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Basic information

Entry
Database: PDB / ID: 3wiy
TitleCrystal structure of Mcl-1 in complex with compound 10
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / REGULATION
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 / 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 / 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-LC6 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsSogabe, S. / Igaki, S. / Hayano, Y.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins.
Authors: Tanaka, Y. / Aikawa, K. / Nishida, G. / Homma, M. / Sogabe, S. / Igaki, S. / Hayano, Y. / Sameshima, T. / Miyahisa, I. / Kawamoto, T. / Tawada, M. / Imai, Y. / Inazuka, M. / Cho, N. / Imaeda, Y. / Ishikawa, T.
History
DepositionSep 26, 2013Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 27, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2014Group: Database references
Revision 1.2Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Induced myeloid leukemia cell differentiation protein Mcl-1
B: Induced myeloid leukemia cell differentiation protein Mcl-1
C: Induced myeloid leukemia cell differentiation protein Mcl-1
D: Induced myeloid leukemia cell differentiation protein Mcl-1
E: Induced myeloid leukemia cell differentiation protein Mcl-1
F: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,55012
Polymers109,2286
Non-polymers5,3226
Water2,486138
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0922
Polymers18,2051
Non-polymers8871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0922
Polymers18,2051
Non-polymers8871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0922
Polymers18,2051
Non-polymers8871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0922
Polymers18,2051
Non-polymers8871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0922
Polymers18,2051
Non-polymers8871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
F: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0922
Polymers18,2051
Non-polymers8871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.288, 65.498, 97.773
Angle α, β, γ (deg.)101.92, 89.83, 99.26
Int Tables number1
Space group name H-MP1

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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: 18204.686 Da / Num. of mol.: 6 / Fragment: UNP RESIDUES 172-327
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Plasmid: pGEX6P1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q07820
#2: Chemical
ChemComp-LC6 / 7-(4-{[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}-2-methylphenyl)-3-[3-(naphthalen-1-yloxy)propyl]pyrazolo[1,5-a]pyridine-2-carboxylic acid


Mass: 887.034 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C47H46N6O8S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 138 / 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: 2.11 Å3/Da / Density % sol: 41.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1M Bis-tris pH 6.5, 22% PEG 3350, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NW12A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Jan 26, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 46298 / % possible obs: 95 % / Redundancy: 2.1 % / Biso Wilson estimate: 27.1 Å2 / Rsym value: 0.081 / Net I/σ(I): 12.1
Reflection shellResolution: 2.09→2.15 Å / Redundancy: 2.1 % / Mean I/σ(I) obs: 1.8 / Rsym value: 0.481 / % possible all: 95.7

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.7.0032refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PQK

2pqk


Resolution: 2.15→36.81 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.906 / SU B: 17.252 / SU ML: 0.208 / Cross valid method: THROUGHOUT / ESU R: 0.369 / ESU R Free: 0.266 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.28293 2335 5.1 %RANDOM
Rwork0.21053 ---
obs0.21419 43840 94.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.997 Å2
Baniso -1Baniso -2Baniso -3
1--0.26 Å2-0.08 Å20.06 Å2
2--1.26 Å20.15 Å2
3----1 Å2
Refinement stepCycle: LAST / Resolution: 2.15→36.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7291 0 378 138 7807
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0197825
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4432.00110552
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0375899
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.72422.767365
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.7151394
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.2891584
X-RAY DIFFRACTIONr_chiral_restr0.0920.21115
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026412
X-RAY DIFFRACTIONr_gen_planes_other
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_it5.2633.7773614
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it6.7276.3314507
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it7.5344.3474211
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined10.84317.28312515
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.15→2.206 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.368 187 -
Rwork0.238 3263 -
obs--94.75 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.45920.53010.24021.05350.41760.74020.03070.0298-0.05940.11470.0292-0.05720.0654-0.0405-0.05990.1022-0.0179-0.03220.035-0.00050.0383-14.6155-4.637729.9402
20.3295-0.54610.12391.12090.05330.69920.04360.0649-0.01220.01790.0277-0.02370.07830.0404-0.07130.05330.0223-0.02720.1395-0.00860.04110.18490.3502-0.009
30.3486-0.3875-0.30280.7705-0.0180.69970.01860.00930.01520.0410.05090.0567-0.06120.0024-0.06950.0737-0.00050.03040.07810.01790.0679-19.677239.205-41.6054
40.3472-0.1206-0.2510.61020.17840.69830.0735-0.08770.0888-0.07280.01220.00420.01210.0011-0.08560.0548-0.03340.01960.0633-0.0290.06826.056127.506321.8335
50.3430.3414-0.22611.727-0.4850.4760.1461-0.08770.0520.1026-0.07730.0514-0.04190.1022-0.06880.0987-0.02780.0340.0849-0.00490.0264-4.95731.7101-12.3724
60.6053-0.2338-0.04830.5295-0.06220.8160.0151-0.0959-0.1742-0.1157-0.02730.0659-0.040.08360.01220.0347-0.0032-0.01420.08390.07430.090111.74425.2755-32.937
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A172 - 323
2X-RAY DIFFRACTION1A501
3X-RAY DIFFRACTION2B172 - 322
4X-RAY DIFFRACTION2B501
5X-RAY DIFFRACTION3C172 - 321
6X-RAY DIFFRACTION3C501
7X-RAY DIFFRACTION4D172 - 321
8X-RAY DIFFRACTION4D501
9X-RAY DIFFRACTION5E172 - 323
10X-RAY DIFFRACTION5E501
11X-RAY DIFFRACTION6F172 - 321
12X-RAY DIFFRACTION6F501

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