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- PDB-6qfm: Structure of human Mcl-1 in complex with PUMA BH3 peptide -

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Basic information

Entry
Database: PDB / ID: 6qfm
TitleStructure of human Mcl-1 in complex with PUMA BH3 peptide
Components
  • Bcl-2-binding component 3
  • Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / MCL1 / BCL2 / PUMA
Function / homology
Function and homology information


positive regulation of establishment of protein localization to mitochondrion / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / positive regulation of fibroblast apoptotic process / T cell apoptotic process / positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / cell fate determination / cellular homeostasis / positive regulation of thymocyte apoptotic process / fibroblast apoptotic process ...positive regulation of establishment of protein localization to mitochondrion / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / positive regulation of fibroblast apoptotic process / T cell apoptotic process / positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / cell fate determination / cellular homeostasis / positive regulation of thymocyte apoptotic process / fibroblast apoptotic process / mitochondrial fusion / Activation of PUMA and translocation to mitochondria / Bcl-2 family protein complex / execution phase of apoptosis / FOXO-mediated transcription of cell death genes / positive regulation of IRE1-mediated unfolded protein response / positive regulation of release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / BH3 domain binding / negative regulation of anoikis / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of intrinsic apoptotic signaling pathway / extrinsic apoptotic signaling pathway in absence of ligand / response to cytokine / intrinsic apoptotic signaling pathway / negative regulation of autophagy / response to endoplasmic reticulum stress / release of cytochrome c from mitochondria / determination of adult lifespan / cellular response to ionizing radiation / apoptotic signaling pathway / positive regulation of protein-containing complex assembly / 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 / cellular response to hypoxia / 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
Bcl-2-binding component 3 / Bcl-2-binding component 3, p53 upregulated modulator of apoptosis / 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 ...Bcl-2-binding component 3 / Bcl-2-binding component 3, p53 upregulated modulator of apoptosis / 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
Induced myeloid leukemia cell differentiation protein Mcl-1 / Bcl-2-binding component 3, isoforms 1/2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsDokurno, P. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Graham, C.J. / Harris, R. / Jordan, A.M. / Matassova, N. / Pedder, C. ...Dokurno, P. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Graham, C.J. / Harris, R. / Jordan, A.M. / Matassova, N. / Pedder, C. / Ray, S. / Roughley, S. / Smith, J. / Walmsley, C. / Wang, Y. / Whitehead, N. / Williamson, D.S. / Casara, P. / Le Diguarher, T. / Hickman, J. / Stark, J. / Kotschy, A. / Geneste, O. / Hubbard, R.E.
CitationJournal: Acs Omega / Year: 2019
Title: Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1.
Authors: Murray, J.B. / Davidson, J. / Chen, I. / Davis, B. / Dokurno, P. / Graham, C.J. / Harris, R. / Jordan, A. / Matassova, N. / Pedder, C. / Ray, S. / Roughley, S.D. / Smith, J. / Walmsley, C. / ...Authors: Murray, J.B. / Davidson, J. / Chen, I. / Davis, B. / Dokurno, P. / Graham, C.J. / Harris, R. / Jordan, A. / Matassova, N. / Pedder, C. / Ray, S. / Roughley, S.D. / Smith, J. / Walmsley, C. / Wang, Y. / Whitehead, N. / Williamson, D.S. / Casara, P. / Le Diguarher, T. / Hickman, J. / Stark, J. / Kotschy, A. / Geneste, O. / Hubbard, R.E.
History
DepositionJan 10, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 12, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 11, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Sep 18, 2019Group: Data collection / Refinement description / Category: software / Item: _software.version
Revision 1.3Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry

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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: Bcl-2-binding component 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,4038
Polymers21,1012
Non-polymers3036
Water1,49583
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2360 Å2
ΔGint-132 kcal/mol
Surface area8080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)36.042, 58.345, 76.922
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 18352.852 Da / Num. of mol.: 1
Mutation: E173D, D241G, L246F, I251V, S255K, T280S, I281V, C286F, S293T, E322Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): pLysS / References: UniProt: Q07820
#2: Protein/peptide Bcl-2-binding component 3 / JFY-1 / p53 up-regulated modulator of apoptosis


Mass: 2747.998 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9BXH1
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / 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: 1.93 Å3/Da / Density % sol: 36.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100 mM imidazole buffer pH 7.0, 50 mM zinc acetate and 20-25% polyethylene glycol (PEG) 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.973 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 12, 2007
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.973 Å / Relative weight: 1
ReflectionResolution: 2→25 Å / Num. obs: 9678 / % possible obs: 84.8 % / Redundancy: 3.2 % / Rmerge(I) obs: 0.079 / Χ2: 1.221 / Net I/σ(I): 10.4 / Num. measured all: 31218
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2-2.072.10.3554480.923140.4
2.07-2.152.30.2876481.055158.3
2.15-2.252.60.288671.137176.9
2.25-2.373.10.259621.101186.8
2.37-2.523.40.20110531.218194.3
2.52-2.713.60.15311121.278198.1
2.71-2.993.50.10511341.175199
2.99-3.423.60.07711321.249198.8
3.42-4.33.50.06311411.392198.1
4.3-253.30.04211811.246194.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0230refinement
SCALEPACKdata scaling
PDB_EXTRACT3.24data extraction
DENZOdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NL9

2nl9


Resolution: 2→9.98 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.915 / SU B: 6.06 / SU ML: 0.162 / SU R Cruickshank DPI: 0.2679 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.268 / ESU R Free: 0.219
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2611 459 4.8 %RANDOM
Rwork0.2022 ---
obs0.2051 9105 83.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 88.18 Å2 / Biso mean: 35.187 Å2 / Biso min: 3.83 Å2
Baniso -1Baniso -2Baniso -3
1--0.38 Å2-0 Å20 Å2
2--0.44 Å2-0 Å2
3----0.06 Å2
Refinement stepCycle: final / Resolution: 2→9.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1278 0 6 83 1367
Biso mean--29.71 39.32 -
Num. residues----160
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0141299
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171156
X-RAY DIFFRACTIONr_angle_refined_deg1.2811.6551749
X-RAY DIFFRACTIONr_angle_other_deg0.9281.6412692
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6915156
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.4872083
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.01315228
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.9671516
X-RAY DIFFRACTIONr_chiral_restr0.070.2165
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021484
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02256
LS refinement shellResolution: 2.004→2.108 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.286 36 -
Rwork0.27 643 -
all-679 -
obs--43.28 %

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