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- PDB-6bw8: Mcl-1 complexed with small molecules -

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Basic information

Entry
Database: PDB / ID: 6bw8
TitleMcl-1 complexed with small molecules
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / Mcl-1 inhibitor / cancer / structure-based design / drug discovery
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / Bcl-2 family protein complex / mitochondrial fusion / BH domain binding / BH3 domain binding / negative regulation of anoikis / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / Bcl-2 family protein complex / mitochondrial fusion / BH domain binding / 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 / release of cytochrome c from mitochondria / negative regulation of autophagy / response to cytokine / intrinsic apoptotic signaling pathway in response to DNA damage / 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 / 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-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 / BCL2-like apoptosis inhibitors family profile. / Apoptosis regulator proteins, Bcl-2 family / Bcl-2-like superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-ECM / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsZhao, B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)BOA29XS129TO22 United States
CitationJournal: J. Med. Chem. / Year: 2018
Title: Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design.
Authors: Shaw, S. / Bian, Z. / Zhao, B. / Tarr, J.C. / Veerasamy, N. / Jeon, K.O. / Belmar, J. / Arnold, A.L. / Fogarty, S.A. / Perry, E. / Sensintaffar, J.L. / Camper, D.V. / Rossanese, O.W. / Lee, ...Authors: Shaw, S. / Bian, Z. / Zhao, B. / Tarr, J.C. / Veerasamy, N. / Jeon, K.O. / Belmar, J. / Arnold, A.L. / Fogarty, S.A. / Perry, E. / Sensintaffar, J.L. / Camper, D.V. / Rossanese, O.W. / Lee, T. / Olejniczak, E.T. / Fesik, S.W.
History
DepositionDec 14, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 31, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 21, 2018Group: Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.name
Revision 1.2Apr 4, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 2023Group: 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

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)74,7688
Polymers71,9184
Non-polymers2,8514
Water00
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6922
Polymers17,9791
Non-polymers7131
Water0
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)18,6922
Polymers17,9791
Non-polymers7131
Water0
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)18,6922
Polymers17,9791
Non-polymers7131
Water0
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)18,6922
Polymers17,9791
Non-polymers7131
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.178, 135.397, 95.750
Angle α, β, γ (deg.)90.00, 90.12, 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: 17979.395 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07820
#2: Chemical
ChemComp-ECM / 7-{8-chloro-11-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl}-1-methyl-1H-indole-3-carboxylic acid


Mass: 712.664 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C39H39Cl2N5O4

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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: 3.74 Å3/Da / Density % sol: 67.12 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 20%-30% PEG3350, Magnesium chloride, Bis-Tris

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 1 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Oct 25, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→40 Å / Num. obs: 19873 / % possible obs: 98.6 % / Observed criterion σ(I): 2 / Redundancy: 3.5 % / CC1/2: 0.994 / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.046 / Rrim(I) all: 0.095 / Rsym value: 0.068 / Χ2: 1.368 / Net I/σ(I): 12.9
Reflection shellResolution: 2.9→2.95 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.328 / Num. unique obs: 846 / Rpim(I) all: 0.227 / Rrim(I) all: 0.403 / Rsym value: 0.388 / % possible all: 76

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZBF

4zbf


Resolution: 2.9→40 Å / Cross valid method: THROUGHOUT / σ(F): 54.42 / Phase error: 27.42
RfactorNum. reflection% reflection
Rfree0.2506 1943 10.77 %
Rwork0.2347 --
obs0.238 19827 89.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.9→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4692 0 200 0 4892
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0064993
X-RAY DIFFRACTIONf_angle_d0.9926759
X-RAY DIFFRACTIONf_dihedral_angle_d5.882904
X-RAY DIFFRACTIONf_chiral_restr0.057718
X-RAY DIFFRACTIONf_plane_restr0.006847
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9009-2.97330.25911310.28451099X-RAY DIFFRACTION69
2.9733-3.05360.30641290.28121199X-RAY DIFFRACTION75
3.0536-3.14330.271290.27121169X-RAY DIFFRACTION77
3.1433-3.24460.27541430.26091259X-RAY DIFFRACTION78
3.2446-3.36030.30611290.25441221X-RAY DIFFRACTION79
3.3603-3.49450.27971460.25141265X-RAY DIFFRACTION80
3.4945-3.65320.25561350.24731290X-RAY DIFFRACTION82
3.6532-3.84520.27951430.24651310X-RAY DIFFRACTION82
3.8452-4.08530.221450.23241295X-RAY DIFFRACTION82
4.0853-4.39930.23641470.23711304X-RAY DIFFRACTION83
4.3993-4.83950.25931420.21311331X-RAY DIFFRACTION83
4.8395-5.53390.25941390.22961296X-RAY DIFFRACTION83
5.5339-6.95020.30351550.24911356X-RAY DIFFRACTION85
6.9502-26.05840.19241580.1991450X-RAY DIFFRACTION90
Refinement TLS params.Method: refined / Origin x: 8.2411 Å / Origin y: 27.777 Å / Origin z: 26.0701 Å
111213212223313233
T0.2684 Å2-0.0327 Å20.0329 Å2-0.3204 Å20.0062 Å2--0.1572 Å2
L0.5688 °20.0849 °20.1665 °2-0.462 °20.1041 °2--0.5861 °2
S0.0672 Å °-0.1104 Å °-0.0791 Å °0.0708 Å °-0.0619 Å °-0.0214 Å °0.106 Å °-0.1522 Å °0.0223 Å °
Refinement TLS groupSelection details: all

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