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- PDB-6qyn: Structure of MBP-Mcl-1 in complex with compound 10d -

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Basic information

Entry
Database: PDB / ID: 6qyn
TitleStructure of MBP-Mcl-1 in complex with compound 10d
ComponentsMaltose/maltodextrin-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 / cell fate determination / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / BH domain binding / detection of maltose stimulus / maltose transport complex / BH3 domain binding / maltose binding ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / BH domain binding / detection of maltose stimulus / maltose transport complex / BH3 domain binding / maltose binding / carbohydrate transport / maltose transport / maltodextrin transmembrane transport / negative regulation of anoikis / protein transmembrane transporter activity / carbohydrate transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / extrinsic apoptotic signaling pathway in absence of ligand / ATP-binding cassette (ABC) transporter complex / negative regulation of autophagy / release of cytochrome c from mitochondria / cell chemotaxis / response to cytokine / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / channel activity / outer membrane-bounded periplasmic space / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / mitochondrial outer membrane / periplasmic space / positive regulation of apoptotic process / protein heterodimerization activity / DNA damage response / negative regulation of apoptotic process / 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-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like ...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-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 / 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-JL8 / Maltose/maltodextrin-binding periplasmic protein / Maltose/maltodextrin-binding periplasmic protein / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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 9, 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 1.2Sep 18, 2019Group: Data collection / Refinement description / Category: software / Item: _software.version
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Non-polymer 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 / struct_conn / 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
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/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,0373
Polymers57,2261
Non-polymers8112
Water3,639202
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area630 Å2
ΔGint2 kcal/mol
Surface area21940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.090, 136.460, 37.990
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/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1 / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Bcl-2-like protein 3 / Bcl2-L- ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Bcl-2-like protein 3 / Bcl2-L-3 / Bcl-2-related protein EAT/mcl1 / mcl1/EAT


Mass: 57225.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820) ...Details: Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820),Protein is a fusion of MBP (UNP P0AEY0) and Mcl-1 (UNP Q07820)
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: malE, Z5632, ECs5017, MCL1, BCL2L3 / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): pLysS
References: UniProt: P0AEY0, UniProt: Q07820, UniProt: P0AEX9*PLUS
#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-JL8 / (2~{R})-2-[5-(3-chloranyl-2-methyl-4-oxidanyl-phenyl)-6-ethyl-thieno[2,3-d]pyrimidin-4-yl]oxy-3-phenyl-propanoic acid


Mass: 468.953 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H21ClN2O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 202 / 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: 2.27 Å3/Da / Density % sol: 45.74 %
Crystal growTemperature: 284 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: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 15, 2015
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.28→50 Å / Num. obs: 42423 / % possible obs: 90.7 % / Redundancy: 2.5 % / Rmerge(I) obs: 0.066 / Net I/σ(I): 11.3
Reflection shellResolution: 2.28→2.42 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.68 / Mean I/σ(I) obs: 1.4 / % possible all: 88.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
PDB_EXTRACT3.24data extraction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LOF

5lof


Resolution: 2.5→20 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.913 / SU B: 11.969 / SU ML: 0.251 / SU R Cruickshank DPI: 1.2632 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.263 / ESU R Free: 0.314
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2513 879 4.7 %RANDOM
Rwork0.1998 ---
obs0.2023 17688 98.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 117.12 Å2 / Biso mean: 42.156 Å2 / Biso min: 15.96 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å2-0 Å2-0 Å2
2---1.41 Å20 Å2
3---1.39 Å2
Refinement stepCycle: final / Resolution: 2.5→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3992 0 55 202 4249
Biso mean--54.43 39.99 -
Num. residues----515
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134140
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173815
X-RAY DIFFRACTIONr_angle_refined_deg1.4431.6425623
X-RAY DIFFRACTIONr_angle_other_deg1.3541.5858835
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8115513
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.41423.719199
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.88615680
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.3491517
X-RAY DIFFRACTIONr_chiral_restr0.070.2545
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.024623
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02833
LS refinement shellResolution: 2.5→2.633 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.488 130 -
Rwork0.419 2440 -
all-2570 -
obs--97.79 %

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