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- PDB-6u65: Mcl-1 bound to compound 19 -

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Basic information

Entry
Database: PDB / ID: 6u65
TitleMcl-1 bound to compound 19
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS/INHIBITOR / anti-apoptotic / inhibitor / PROTEIN BINDING / APOPTOSIS-INHIBITOR complex
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
ACETATE ION / DI(HYDROXYETHYL)ETHER / Chem-Q0A / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09 Å
AuthorsStuckey, J.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01-CA-217141-01 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 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)74,30721
Polymers71,3534
Non-polymers2,95417
Water3,387188
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6166
Polymers17,8381
Non-polymers7785
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)18,5485
Polymers17,8381
Non-polymers7104
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)18,6546
Polymers17,8381
Non-polymers8165
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)18,4894
Polymers17,8381
Non-polymers6513
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)69.712, 85.223, 109.753
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 4 molecules ABCD

#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.: 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

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Non-polymers , 5 types, 205 molecules

#2: Chemical
ChemComp-Q0A / 2-[({4-[(4-fluorophenyl)methyl]piperazin-1-yl}sulfonyl)amino]-5-[(2-phenylethyl)sulfanyl]benzoic acid


Mass: 529.647 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H28FN3O4S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 188 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.33 Å3/Da / Density % sol: 47.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 18% PEG 3350, 200 mM NH4 Acetate, 100 mM Bis-Tris pH 6.5

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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: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 6, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.09→50 Å / Num. obs: 39233 / % possible obs: 100 % / Redundancy: 7.4 % / Biso Wilson estimate: 31.82 Å2 / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.025 / Rrim(I) all: 0.069 / Χ2: 0.69 / Net I/av σ(I): 19.98 / Net I/σ(I): 10.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.1-2.147.50.43219300.9240.170.4640.829100
2.14-2.187.50.35219270.9510.1380.3790.809100
2.18-2.227.50.29819130.9610.1170.320.809100
2.22-2.267.50.26219520.9730.1030.2810.793100
2.26-2.317.50.23519270.9770.0920.2520.79100
2.31-2.377.50.19219270.9840.0750.2060.771100
2.37-2.427.50.17519410.9860.0680.1880.768100
2.42-2.497.50.1619390.9880.0630.1720.794100
2.49-2.567.50.14319590.990.0560.1530.799100
2.56-2.657.50.12519120.9930.0490.1350.786100
2.65-2.747.50.1119720.9930.0430.1190.767100
2.74-2.857.40.09719320.9950.0380.1040.723100
2.85-2.987.50.08419680.9960.0330.090.655100
2.98-3.147.40.07119380.9960.0280.0770.642100
3.14-3.337.40.06419880.9970.0250.0690.674100
3.33-3.597.40.05619620.9970.0220.060.604100
3.59-3.957.40.05519900.9970.0220.0590.731100
3.95-4.527.30.03619870.9990.0140.0390.416100
4.52-5.77.20.02920290.9990.0110.0310.285100
5.7-506.70.03421400.9980.0140.0370.33699.6

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
BUSTER-TNT2.10.0refinement
PDB_EXTRACT3.2data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.09→43.12 Å / Cor.coef. Fo:Fc: 0.9455 / Cor.coef. Fo:Fc free: 0.9357 / SU R Cruickshank DPI: 0.205 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.207 / SU Rfree Blow DPI: 0.166 / SU Rfree Cruickshank DPI: 0.167
RfactorNum. reflection% reflectionSelection details
Rfree0.2215 1945 4.97 %RANDOM
Rwork0.1874 ---
obs0.1891 39167 99.33 %-
Displacement parametersBiso max: 127.94 Å2 / Biso mean: 37.55 Å2 / Biso min: 14.58 Å2
Baniso -1Baniso -2Baniso -3
1-2.5277 Å20 Å20 Å2
2---1.0362 Å20 Å2
3----1.4915 Å2
Refine analyzeLuzzati coordinate error obs: 0.255 Å
Refinement stepCycle: final / Resolution: 2.09→43.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4691 0 199 188 5078
Biso mean--38.79 42.77 -
Num. residues----603
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2362SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes113HARMONIC2
X-RAY DIFFRACTIONt_gen_planes828HARMONIC5
X-RAY DIFFRACTIONt_it5007HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion639SEMIHARMONIC5
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_contact6084SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5007HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6750HARMONIC20.9
X-RAY DIFFRACTIONt_omega_torsion2.59
X-RAY DIFFRACTIONt_other_torsion2.83
LS refinement shellResolution: 2.09→2.14 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2504 124 4.74 %
Rwork0.1855 2491 -
all0.1886 2615 -
obs--99.33 %
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)
16.22251.88541.54772.7866-0.21482.2347-0.32640.46540.8790.02350.0480.1238-0.29940.23660.2784-0.0488-0.0218-0.0151-0.07950.11930.049117.86461.8519-10.0217
22.62080.0277-0.10551.2315-0.58931.7857-0.01710.073-0.0581-0.0052-0.0834-0.1270.02560.25010.1004-0.04760.0004-0.0108-0.03270.0468-0.034324.2721-12.2082-4.9787
36.81941.05981.59723.52480.4063.42360.0873-0.28380.37840.0418-0.12220.3362-0.238-0.22540.0349-0.0920.0090.0221-0.03560.01180.00316.4419-5.397-5.3573
40.84690.1851-1.41230.90630.40543.2467-0.1202-0.3959-0.04240.30530.0653-0.0565-0.00960.04630.05490.0155-0.0039-0.00840.04330.0413-0.081424.5274-23.568529.5715
52.04310.1758-0.38110.8457-0.47931.4359-0.0247-0.0168-0.10660.12460.04820.02120.0179-0.1245-0.0235-0.03950.00960.0013-0.03070.0367-0.056420.8524-24.356514.0779
64.11780.2320.48122.6062-1.33432.91080.1239-0.47260.26540.13440.0109-0.3057-0.40180.4642-0.1347-0.0623-0.0749-0.03610.0711-0.0186-0.002436.6662-18.039122.7731
72.63270.11830.05152.7413-0.02122.11590.09130.21850.2421-0.18030.04040.0248-0.3435-0.1216-0.13160.0417-0.0046-0.0356-0.10410.0127-0.113548.12217.2685-2.3364
81.39210.1378-0.30162.31160.90282.215-0.02930.2613-0.1962-0.20820.0999-0.21790.05450.0546-0.0706-0.0249-0.0123-0.0743-0.0478-0.0322-0.022151.88875.1347-3.8541
91.67960.63752.75520.58370.3255.18660.08970.0479-0.00810.2303-0.05090.4023-0.3888-0.7413-0.0388-0.02340.06410.01350.0317-0.0128-0.03137.657815.42147.1219
102.98471.6343-0.93021.8556-0.47774.36050.1023-0.3204-0.09610.0490.029-0.13010.70090.5203-0.13120.08990.0955-0.11070.1186-0.0387-0.038370.5539-1.176829.1787
113.7656-0.25361.38870.63790.35835.36960.2815-0.1013-0.45690.06790.11740.1640.66940.0638-0.3989-0.06130.0343-0.112-0.1784-0.0311-0.120562.1741-1.771318.4178
127.676-2.1641-0.94010-2.46236.36670.19120.13980.3408-0.1825-0.1581-0.35830.04871.0576-0.0331-0.1480.03210.00710.0895-0.0745-0.118777.65514.290116.3112
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|172 - 217}A172 - 217
2X-RAY DIFFRACTION2{A|218 - 299}A218 - 299
3X-RAY DIFFRACTION3{A|300 - 321}A300 - 321
4X-RAY DIFFRACTION4{B|172 - 213}B172 - 213
5X-RAY DIFFRACTION5{B|214 - 301}B214 - 301
6X-RAY DIFFRACTION6{B|302 - 321}B302 - 321
7X-RAY DIFFRACTION7{C|170 - 230}C170 - 230
8X-RAY DIFFRACTION8{C|231 - 302}C231 - 302
9X-RAY DIFFRACTION9{C|303 - 322}C303 - 322
10X-RAY DIFFRACTION10{D|172 - 203}D172 - 203
11X-RAY DIFFRACTION11{D|204 - 297}D204 - 297
12X-RAY DIFFRACTION12{D|298 - 321}D298 - 321

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