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- PDB-6qxj: Structure of MBP-Mcl-1 in complex with compound 6a -

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Basic information

Entry
Database: PDB / ID: 6qxj
TitleStructure of MBP-Mcl-1 in complex with compound 6a
ComponentsMaltose-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / Apoptosis-inhibitor complex / Mcl1 / Small molecule inhibitor / MBP
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 / carbohydrate transmembrane transporter activity / negative regulation of anoikis ...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 / carbohydrate 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 / outer membrane-bounded periplasmic space / 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 / 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 ...Apoptosis regulator, Mcl-1 / 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 / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein
Similarity search - Domain/homology
alpha-maltose / Chem-JKQ / Maltose/maltodextrin-binding periplasmic protein / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesEscherichia coli O157:H7 (bacteria)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsDokurno, P. / Szlavik, Z. / Ondi, L. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Radics, G. / Murray, J. / Davidson, J. / Chen, I. ...Dokurno, P. / Szlavik, Z. / Ondi, L. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Radics, G. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Hubbard, R.E. / Pedder, C. / Surgenor, A.E. / Smith, J. / Robertson, A. / LeToumelin-Braizat, G. / Cauquil, N. / Zarka, M. / Demarles, D. / Perron-Sierra, F. / Geneste, O. / Kotschy, A.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity.
Authors: Szlavik, Z. / Ondi, L. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Radics, G. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Hubbard, R.E. / Pedder, C. / Dokurno, P. / Surgenor, A. / ...Authors: Szlavik, Z. / Ondi, L. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Radics, G. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Hubbard, R.E. / Pedder, C. / Dokurno, P. / Surgenor, A. / Smith, J. / Robertson, A. / LeToumelin-Braizat, G. / Cauquil, N. / Zarka, M. / Demarles, D. / Perron-Sierra, F. / Claperon, A. / Colland, F. / Geneste, O. / Kotschy, A.
History
DepositionMar 7, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 7, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 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_author.identifier_ORCID
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Non-polymer description / Refinement description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / entity_name_com / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_molecule_features / pdbx_nonpoly_scheme / pdbx_struct_conn_angle / software / struct_conn / struct_conn_type / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.src_method / _entity.type / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _software.version
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _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: Maltose-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,9584
Polymers57,2261
Non-polymers7323
Water6,341352
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area760 Å2
ΔGint-5 kcal/mol
Surface area21610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.210, 135.950, 37.800
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Maltose-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1 / MBP / MMBP / Maltodextrin-binding protein / Bcl-2-like protein 3 / Bcl2-L-3 / Bcl-2-related protein ...MBP / MMBP / Maltodextrin-binding protein / Bcl-2-like protein 3 / Bcl2-L-3 / Bcl-2-related protein EAT/mcl1 / mcl1/EAT


Mass: 57225.867 Da / Num. of mol.: 1 / Mutation: K194A, K197A, R201A,K194A, K197A, R201A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli O157:H7 (bacteria), (gene. exp.) Homo sapiens (human)
Gene: malE, Z5632, ECs5017, MCL1, BCL2L3 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / Variant (production host): pLysS / References: UniProt: P0AEY0, UniProt: Q07820
#2: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose / alpha-maltose


Type: oligosaccharide, Oligosaccharide / Class: Nutrient / Mass: 342.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: oligosaccharide / References: alpha-maltose
DescriptorTypeProgram
DGlcpa1-4DGlcpa1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1a_1-5]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][a-D-Glcp]{[(4+1)][a-D-Glcp]{}}LINUCSPDB-CARE
#3: Chemical ChemComp-JKQ / (2~{R})-2-[[6-ethyl-5-(1~{H}-indol-5-yl)thieno[2,3-d]pyrimidin-4-yl]amino]propanoic acid


Mass: 366.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18N4O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 352 / 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: 2.23 Å3/Da / Density % sol: 44.78 %
Crystal growTemperature: 279 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 25% PEG3350, 0.2M MAGNESIUM FORMATE,1MM MALTOSE

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 27, 2017
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.59→45.3 Å / Num. obs: 67671 / % possible obs: 97.2 % / Redundancy: 3.8 % / Rmerge(I) obs: 0.033 / Net I/σ(I): 17.3

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Processing

Software
NameVersionClassification
XDSdata reduction
REFMAC5.8.0158refinement
PDB_EXTRACT3.24data extraction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LOF

5lof


Resolution: 1.7→20 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.964 / SU B: 2.252 / SU ML: 0.073 / SU R Cruickshank DPI: 0.104 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.104 / ESU R Free: 0.101
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.203 2829 5 %RANDOM
Rwork0.1717 ---
obs0.1733 53732 98.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 107.78 Å2 / Biso mean: 37.229 Å2 / Biso min: 18.3 Å2
Baniso -1Baniso -2Baniso -3
1-1.24 Å20 Å2-0 Å2
2---1.64 Å20 Å2
3---0.4 Å2
Refinement stepCycle: final / Resolution: 1.7→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3981 0 50 352 4383
Biso mean--47.95 43.77 -
Num. residues----513
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0194135
X-RAY DIFFRACTIONr_bond_other_d0.0020.023829
X-RAY DIFFRACTIONr_angle_refined_deg2.0071.965616
X-RAY DIFFRACTIONr_angle_other_deg1.1242.9948896
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3645515
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.10924.972181
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.97915688
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.3611517
X-RAY DIFFRACTIONr_chiral_restr0.2070.2621
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0214610
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02824
LS refinement shellResolution: 1.7→1.791 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.271 422 -
Rwork0.243 7691 -
all-8113 -
obs--98.66 %

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