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- PDB-3wix: Crystal structure of Mcl-1 in complex with compound 4 -

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Basic information

Entry
Database: PDB / ID: 3wix
TitleCrystal structure of Mcl-1 in complex with compound 4
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 / cellular homeostasis / cell fate determination / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / protein transmembrane transporter activity / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand ...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 / protein transmembrane transporter activity / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / 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 / 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 / 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 (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-LC3 / 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
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,6858
Polymers72,8194
Non-polymers1,8664
Water1,42379
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6712
Polymers18,2051
Non-polymers4661
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)18,6712
Polymers18,2051
Non-polymers4661
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)18,6712
Polymers18,2051
Non-polymers4661
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)18,6712
Polymers18,2051
Non-polymers4661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.169, 133.829, 58.243
Angle α, β, γ (deg.)90.00, 89.94, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 4 / 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-LC3 / 7-(4-carboxyphenyl)-3-[3-(naphthalen-1-yloxy)propyl]pyrazolo[1,5-a]pyridine-2-carboxylic acid


Mass: 466.485 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H22N2O5
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.04 Å3/Da / Density % sol: 39.79 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1M Tris pH 8.0, 0.2M sodium isothiocyanate, 20% 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-NE3A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Oct 29, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 41960 / % possible obs: 91.3 % / Redundancy: 3.4 % / Biso Wilson estimate: 28 Å2 / Rsym value: 0.072 / Net I/σ(I): 18.8
Reflection shellResolution: 1.9→1.93 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 1.9 / Rsym value: 0.524 / % possible all: 93.7

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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: 1.9→29.02 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.894 / SU B: 11.554 / SU ML: 0.159 / Cross valid method: THROUGHOUT / ESU R: 0.241 / ESU R Free: 0.205 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.29095 2128 5.1 %RANDOM
Rwork0.24342 ---
obs0.24583 39802 91.18 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.148 Å2
Baniso -1Baniso -2Baniso -3
1-3.59 Å2-0 Å2-0.25 Å2
2---1.33 Å20 Å2
3----2.27 Å2
Refinement stepCycle: LAST / Resolution: 1.9→29.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4735 0 140 79 4954
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0194967
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4281.9746688
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2685581
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.90122.773238
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.87915901
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6361554
X-RAY DIFFRACTIONr_chiral_restr0.0920.2724
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.023950
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_it3.5572.5552342
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.6254.2812917
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.7362.9862625
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined7.44412.0537905
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: 1.899→1.948 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 154 -
Rwork0.292 2954 -
obs--91.9 %
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)
10.77170.07360.30312.9771-0.43042.66250.11330.01120.0084-0.0449-0.0288-0.09120.16290.0719-0.08450.0288-0.0110.02030.1259-0.01070.1071-9.13120.0151-49.1875
20.85230.51-0.38473.74910.31183.92760.06410.00220.0147-0.2757-0.01050.1723-0.3109-0.2614-0.05360.04820.0138-0.01090.21980.00510.1603-22.1611-1.5995-20.0747
31.63330.50240.42382.063-0.44562.8522-0.0179-0.1301-0.1836-0.16830.0122-0.08260.19620.05660.00570.0242-0.00380.01790.140.00320.1696-6.0812-29.3686-28.6838
41.61340.7492-0.09473.0859-0.14053.1233-0.05040.08520.2044-0.07170.08180.1388-0.1677-0.0514-0.03130.0995-0.0190.00180.09440.02940.1213-25.14527.68961.0058
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A172 - 321
2X-RAY DIFFRACTION1A501
3X-RAY DIFFRACTION2B172 - 321
4X-RAY DIFFRACTION2B501
5X-RAY DIFFRACTION3C172 - 321
6X-RAY DIFFRACTION3C501
7X-RAY DIFFRACTION4D172 - 321
8X-RAY DIFFRACTION4D501

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