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- PDB-6u67: Mcl-1 bound to compound 24 -

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Basic information

Entry
Database: PDB / ID: 6u67
TitleMcl-1 bound to compound 24
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 / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity ...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 / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of autophagy / release of cytochrome c from mitochondria / response to cytokine / Signaling by ALK fusions and activated point mutants / 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
BIPHENYL / Chem-Q01 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.84 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,56510
Polymers35,6762
Non-polymers3,8898
Water3,243180
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,7835
Polymers17,8381
Non-polymers1,9444
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)19,7835
Polymers17,8381
Non-polymers1,9444
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.514, 134.376, 70.794
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11B-511-

HOH

21B-582-

HOH

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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.: 2
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-Q01 / 2-({[4-(4-tert-butylphenyl)piperazin-1-yl]sulfonyl}amino)-5-{[3-oxo-3-(phenylamino)propyl]sulfanyl}benzoic acid


Mass: 596.761 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C30H36N4O5S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-BNL / BIPHENYL


Mass: 154.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H10
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 180 / 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: 2.25 Å3/Da / Density % sol: 45.34 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 20% (w/v) PEG-1000, 0.1 M Tris pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9786 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: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.84→50 Å / Num. obs: 28285 / % possible obs: 99.8 % / Redundancy: 7.2 % / Biso Wilson estimate: 25.57 Å2 / Rmerge(I) obs: 0.054 / Rpim(I) all: 0.022 / Rrim(I) all: 0.059 / Χ2: 0.665 / Net I/σ(I): 11.9 / Num. measured all: 202344
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.84-1.8760.33313670.9680.1460.3650.70498.2
1.87-1.916.70.29513740.9750.1220.320.71199.7
1.91-1.947.20.26613900.9830.1060.2870.745100
1.94-1.987.30.21714240.990.0860.2340.728100
1.98-2.037.30.1814010.9930.0710.1940.71100
2.03-2.077.30.16313800.9930.0640.1750.72100
2.07-2.127.30.13713990.9950.0540.1480.674100
2.12-2.187.30.11514020.9960.0460.1240.661100
2.18-2.257.30.10314070.9970.0410.1110.679100
2.25-2.327.30.0913970.9970.0360.0970.699100
2.32-2.47.30.08914080.9960.0350.0960.755100
2.4-2.57.30.09214200.9960.0370.0990.82100
2.5-2.617.30.08214040.9960.0320.0880.781100
2.61-2.757.30.06614180.9980.0260.0710.685100
2.75-2.927.30.05514200.9980.0220.060.585100
2.92-3.157.30.05414220.9980.0210.0580.624100
3.15-3.467.30.0514310.9980.020.0540.62100
3.46-3.967.20.04814500.9980.0190.0520.72100
3.96-4.9970.0314450.9990.0120.0320.362100
4.99-506.60.02815260.9990.0120.030.31999

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
BUSTER2.10.3refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.84→22.57 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.917 / SU R Cruickshank DPI: 0.141 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.146 / SU Rfree Blow DPI: 0.129 / SU Rfree Cruickshank DPI: 0.128
RfactorNum. reflection% reflectionSelection details
Rfree0.222 1386 4.91 %RANDOM
Rwork0.191 ---
obs0.192 28248 99.7 %-
Displacement parametersBiso max: 112.93 Å2 / Biso mean: 32.83 Å2 / Biso min: 13.11 Å2
Baniso -1Baniso -2Baniso -3
1--14.8563 Å20 Å20 Å2
2--7.9199 Å20 Å2
3---6.9364 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 1.84→22.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2394 0 185 180 2759
Biso mean--34.07 40.55 -
Num. residues----302
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1246SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes531HARMONIC5
X-RAY DIFFRACTIONt_it2647HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion322SEMIHARMONIC5
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_contact3339SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2647HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3580HARMONIC20.88
X-RAY DIFFRACTIONt_omega_torsion2.74
X-RAY DIFFRACTIONt_other_torsion2.97
LS refinement shellResolution: 1.84→1.85 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.259 36 6.37 %
Rwork0.1884 529 -
all0.1928 565 -
obs--90.53 %
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)
11.03730.15860.07762.48960.93531.2840.10860.0916-0.1392-0.1816-0.061-0.26830.07150.0181-0.0475-0.02890.04790.0357-0.0525-0.0032-0.0319.882833.10184.0622
20.6382-0.08130.31661.2764-0.53122.0498-0.0207-0.06210.07580.0108-0.13-0.2992-0.30130.16860.1507-0.0023-0.0342-0.0072-0.05070.0325-0.01116.626664.973416.4182
30-0.5576-0.58351.5781-0.623700.0789-0.0697-0.02240.0176-0.2112-0.021-0.0154-0.04860.13220.01840.0055-0.0160.01520.0285-0.03885.58449.768815.1268
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|172 - A|321 }A172 - 321
2X-RAY DIFFRACTION2{ B|170 - B|321 }B170 - 321
3X-RAY DIFFRACTION3{ A|401 - A|403 B|401 - B|403 }A401 - 403
4X-RAY DIFFRACTION3{ A|401 - A|403 B|401 - B|403 }B401 - 403

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