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- PDB-6p3p: Crystal structure of Mcl-1 in complex with compound 65 -

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Basic information

Entry
Database: PDB / ID: 6p3p
TitleCrystal structure of Mcl-1 in complex with compound 65
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS/APOPTOSIS INHIBITOR / Mcl-1 / biaryl sulfonamide inhibitor / APOPTOSIS-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 / 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 ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / 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 / response to cytokine / negative regulation of autophagy / release of cytochrome c from mitochondria / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / positive regulation of neuron apoptotic process / 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 / nucleus / membrane / 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-NQJ / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.61 Å
AuthorsToms, A.V. / Follows, B.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors.
Authors: Follows, B. / Fessler, S. / Baumeister, T. / Campbell, A.M. / Zablocki, M.M. / Li, H. / Gotur, D. / Wang, Z. / Zheng, X. / Molz, L. / Nguyen, C. / Herbertz, T. / Wang, L. / Bair, K.
History
DepositionMay 24, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 3, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Aug 21, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 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

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Assembly

Deposited unit
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4412
Polymers17,8801
Non-polymers5611
Water1,78399
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.229, 48.245, 40.707
Angle α, β, γ (deg.)90.00, 108.50, 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: 17880.307 Da / Num. of mol.: 1 / Mutation: E171S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q07820
#2: Chemical ChemComp-NQJ / methyl N-(5-{[2-chloro-5-(trifluoromethyl)phenyl]sulfamoyl}-4-methylthiophene-2-carbonyl)-D-phenylalaninate


Mass: 560.994 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20ClF3N2O5S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / 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: 1.99 Å3/Da / Density % sol: 38.22 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 100 mM Bicine pH 8.5, 35% PEG 1500 and 10% ethanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 17, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 1.61→50 Å / Num. obs: 17834 / % possible obs: 99 % / Redundancy: 3.5 % / CC1/2: 0.991 / Rsym value: 0.058 / Net I/σ(I): 18.9
Reflection shellResolution: 1.61→1.67 Å / Redundancy: 3.2 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1118 / CC1/2: 0.734 / Rsym value: 0.53 / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3mk8

3mk8


Resolution: 1.61→38.6 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.946 / SU B: 2.057 / SU ML: 0.071 / Cross valid method: THROUGHOUT / ESU R: 0.109 / ESU R Free: 0.101 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21347 907 5.1 %RANDOM
Rwork0.18997 ---
obs0.19119 16917 97.16 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 23.525 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å2-0 Å20.01 Å2
2--0.03 Å2-0 Å2
3----0 Å2
Refinement stepCycle: 1 / Resolution: 1.61→38.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1189 0 36 99 1324
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0191312
X-RAY DIFFRACTIONr_bond_other_d0.0010.021215
X-RAY DIFFRACTIONr_angle_refined_deg1.3851.9671780
X-RAY DIFFRACTIONr_angle_other_deg0.90732793
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.0985161
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.63222.34464
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.81615232
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.781516
X-RAY DIFFRACTIONr_chiral_restr0.0650.2192
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021489
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02306
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_it1.1442.227626
X-RAY DIFFRACTIONr_mcbond_other1.1352.225625
X-RAY DIFFRACTIONr_mcangle_it1.8663.338790
X-RAY DIFFRACTIONr_mcangle_other1.8653.34791
X-RAY DIFFRACTIONr_scbond_it1.5122.453686
X-RAY DIFFRACTIONr_scbond_other1.5112.453687
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.5063.603990
X-RAY DIFFRACTIONr_long_range_B_refined4.23927.411603
X-RAY DIFFRACTIONr_long_range_B_other4.14527.0091581
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.609→1.651 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 64 -
Rwork0.287 1118 -
obs--87.3 %

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