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- PDB-6u6f: The crystal structure of anti-apoptotic Mcl-1 protein in complex ... -

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Basic information

Entry
Database: PDB / ID: 6u6f
TitleThe crystal structure of anti-apoptotic Mcl-1 protein in complex with 2, 5-substituted benzoic acid inhibitor 21
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS/INHIBITOR / Apoptosis / Mcl1 / Bfl1/A1 / protein-protein interaction / BH3 mimetics / cancer / APOPTOSIS-INHIBITOR complex
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 / 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 / mitochondrial fusion / Bcl-2 family protein complex / 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 / 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 / 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 / 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-PZY / 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
AuthorsYang, Y. / Stuckey, J.A. / Nikolovska-Coleska, Z.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA-149442 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R21 NS056915 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30 CA046592 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins.
Authors: Kump, K.J. / Miao, L. / Mady, A.S.A. / Ansari, N.H. / Shrestha, U.K. / Yang, Y. / Pal, M. / Liao, C. / Perdih, A. / Abulwerdi, F.A. / Chinnaswamy, K. / Meagher, J.L. / Carlson, J.M. / ...Authors: Kump, K.J. / Miao, L. / Mady, A.S.A. / Ansari, N.H. / Shrestha, U.K. / Yang, Y. / Pal, M. / Liao, C. / Perdih, A. / Abulwerdi, F.A. / Chinnaswamy, K. / Meagher, J.L. / Carlson, J.M. / Khanna, M. / Stuckey, J.A. / Nikolovska-Coleska, Z.
History
DepositionAug 29, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 25, 2020Group: 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 1.2Oct 11, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,7867
Polymers53,5153
Non-polymers2,2714
Water93752
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,9743
Polymers17,8381
Non-polymers1,1362
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)18,4062
Polymers17,8381
Non-polymers5681
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)18,4062
Polymers17,8381
Non-polymers5681
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)68.450, 68.450, 363.650
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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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: 17838.229 Da / Num. of mol.: 3
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-PZY / 2-[({4-[(4-tert-butylphenyl)methyl]piperazin-1-yl}sulfonyl)amino]-5-[(2-phenylethyl)sulfanyl]benzoic acid


Mass: 567.762 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C30H37N3O4S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 52 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.3 Å3/Da / Density % sol: 46.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: PEG3350 20-22.5%, 0.1 M Bis-Tris 6.5, 0.28 M Ammonium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Aug 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.9→200 Å / Num. obs: 12245 / % possible obs: 99.9 % / Redundancy: 18 % / Biso Wilson estimate: 71.33 Å2 / Rmerge(I) obs: 0.12 / Rpim(I) all: 0.028 / Rrim(I) all: 0.124 / Χ2: 1.095 / Net I/σ(I): 6.6 / Num. measured all: 220047
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.9-2.9516.80.7065820.9270.170.7270.695100
2.95-316.90.5315840.960.1280.5480.736100
3-3.0616.90.4495830.9830.1080.4620.761100
3.06-3.1216.20.4136130.9750.10.4260.805100
3.12-3.1917.40.3585690.9790.0860.3690.885100
3.19-3.2716.80.3146000.9830.0760.3240.865100
3.27-3.35170.2885740.9870.070.2970.927100
3.35-3.4416.80.2536050.9830.0610.2611.029100
3.44-3.5417.20.2025870.9930.0490.2081.089100
3.54-3.6517.10.1695890.9960.0410.1741.118100
3.65-3.78170.1366220.9960.0330.141.174100
3.78-3.9417.20.1255900.9950.030.1281.243100
3.94-4.1217.50.116060.9970.0260.1131.136100
4.12-4.3317.60.16090.9980.0240.1031.279100
4.33-4.618.50.0996160.9980.0240.1021.359100
4.6-4.9619.10.1026230.9960.0240.1051.305100
4.96-5.4620.10.0916200.9980.0210.0941.296100
5.46-6.2521.20.0886540.9980.0190.091.206100
6.25-7.8721.60.0736590.9980.0160.0751.283100
7.87-20019.20.0557600.9990.0120.0561.29898.6

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Processing

Software
NameVersionClassification
HKL-2000data scaling
BUSTER2.10.3refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PQK

2pqk


Resolution: 2.9→36.07 Å / Cor.coef. Fo:Fc: 0.909 / Cor.coef. Fo:Fc free: 0.861 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.457
RfactorNum. reflection% reflectionSelection details
Rfree0.279 590 4.87 %RANDOM
Rwork0.238 ---
obs0.24 12127 99.9 %-
Displacement parametersBiso max: 125.44 Å2 / Biso mean: 52.78 Å2 / Biso min: 24.15 Å2
Baniso -1Baniso -2Baniso -3
1--3.6051 Å20 Å20 Å2
2---3.6051 Å20 Å2
3---7.2102 Å2
Refine analyzeLuzzati coordinate error obs: 0.45 Å
Refinement stepCycle: final / Resolution: 2.9→36.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3494 0 140 52 3686
Biso mean--50.8 41.79 -
Num. residues----456
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1288SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes630HARMONIC5
X-RAY DIFFRACTIONt_it3704HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion477SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4382SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3704HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg5022HARMONIC20.89
X-RAY DIFFRACTIONt_omega_torsion1.74
X-RAY DIFFRACTIONt_other_torsion19.13
LS refinement shellResolution: 2.9→2.94 Å / Rfactor Rfree error: 0 / Total num. of bins used: 29
RfactorNum. reflection% reflection
Rfree0.3118 12 2.86 %
Rwork0.291 407 -
all0.2917 419 -
obs--100 %

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