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- PDB-5lof: Crystal structure of the MBP-MCL1 complex with highly selective a... -

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Basic information

Entry
Database: PDB / ID: 5lof
TitleCrystal structure of the MBP-MCL1 complex with highly selective and potent inhibitor of MCL1
ComponentsMaltose-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS/INHIBITOR / APOPTOSIS-INHIBITOR COMPLEX / MCL-1 / S S63845 / MBP
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / mitochondrial fusion / channel activity / Bcl-2 family protein complex / BH3 domain binding / maltose binding / maltose transport / maltodextrin transmembrane transport ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / mitochondrial fusion / channel activity / Bcl-2 family protein complex / BH3 domain binding / maltose binding / maltose transport / maltodextrin transmembrane transport / carbohydrate transmembrane transporter activity / negative regulation of anoikis / protein 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 / 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 / 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-70R / 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: 2.2 Å
AuthorsDokurno, P. / Kotschy, A. / Szlavik, Z. / Murray, J. / Davidson, J. / Csekei, M. / Paczal, A. / Szabo, Z. / Sipos, S. / Radics, G. ...Dokurno, P. / Kotschy, A. / Szlavik, Z. / Murray, J. / Davidson, J. / Csekei, M. / Paczal, A. / Szabo, Z. / Sipos, S. / Radics, G. / Proszenyak, A. / Balint, B. / Ondi, L. / Blasko, G. / Robertson, A. / Surgenor, A. / Chen, I. / Matassova, N. / Smith, J. / Pedder, C. / Graham, C. / Geneste, O.
CitationJournal: Nature / Year: 2016
Title: The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.
Authors: Kotschy, A. / Szlavik, Z. / Murray, J. / Davidson, J. / Maragno, A.L. / Le Toumelin-Braizat, G. / Chanrion, M. / Kelly, G.L. / Gong, J.N. / Moujalled, D.M. / Bruno, A. / Csekei, M. / Paczal, ...Authors: Kotschy, A. / Szlavik, Z. / Murray, J. / Davidson, J. / Maragno, A.L. / Le Toumelin-Braizat, G. / Chanrion, M. / Kelly, G.L. / Gong, J.N. / Moujalled, D.M. / Bruno, A. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Sipos, S. / Radics, G. / Proszenyak, A. / Balint, B. / Ondi, L. / Blasko, G. / Robertson, A. / Surgenor, A. / Dokurno, P. / Chen, I. / Matassova, N. / Smith, J. / Pedder, C. / Graham, C. / Studeny, A. / Lysiak-Auvity, G. / Girard, A.M. / Grave, F. / Segal, D. / Riffkin, C.D. / Pomilio, G. / Galbraith, L.C. / Aubrey, B.J. / Brennan, M.S. / Herold, M.J. / Chang, C. / Guasconi, G. / Cauquil, N. / Melchiore, F. / Guigal-Stephan, N. / Lockhart, B. / Colland, F. / Hickman, J.A. / Roberts, A.W. / Huang, D.C. / Wei, A.H. / Strasser, A. / Lessene, G. / Geneste, O.
History
DepositionAug 9, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 26, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 2, 2016Group: Database references
Revision 1.2Nov 9, 2016Group: Database references
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 10, 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)58,3973
Polymers57,2261
Non-polymers1,1722
Water3,297183
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area630 Å2
ΔGint2 kcal/mol
Surface area21760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.400, 136.760, 38.330
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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-70R / (2~{R})-2-[5-[3-chloranyl-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(5-fluoranylfuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[2,2,2-tris(fluoranyl)ethyl]pyrazol-3-yl]methoxy]phenyl]propanoic acid


Mass: 829.259 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H37ClF4N6O6S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 183 / 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: 2.3 Å3/Da / Density % sol: 46.5 % / Description: rod-like
Crystal growTemperature: 284 K / Method: vapor diffusion, sitting drop / Details: 25% PEG3350, 0.2M Magnesium Formate, 1mM Maltose

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.17→50 Å / Num. obs: 28314 / % possible obs: 99 % / Observed criterion σ(F): 1 / Redundancy: 4.5 % / Biso Wilson estimate: 46.8 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.057 / Net I/σ(I): 16.7
Reflection shellResolution: 2.17→2.3 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.52 / Mean I/σ(I) obs: 2.2 / CC1/2: 0.909 / % possible all: 97.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0151refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WGI

4wgi


Resolution: 2.2→50 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.94 / SU B: 7.421 / SU ML: 0.177 / Cross valid method: THROUGHOUT / ESU R: 0.279 / ESU R Free: 0.213 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23525 1336 4.9 %RANDOM
Rwork0.18107 ---
obs0.18379 25921 99.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 47.536 Å2
Baniso -1Baniso -2Baniso -3
1-3.01 Å20 Å2-0 Å2
2---4.52 Å20 Å2
3---1.51 Å2
Refinement stepCycle: 1 / Resolution: 2.2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3975 0 80 183 4238
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0194149
X-RAY DIFFRACTIONr_bond_other_d0.0020.023909
X-RAY DIFFRACTIONr_angle_refined_deg1.6471.9595638
X-RAY DIFFRACTIONr_angle_other_deg1.0092.9879008
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7215512
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.26624.972181
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.81215678
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.7341517
X-RAY DIFFRACTIONr_chiral_restr0.0940.2623
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214690
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02910
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_it3.5084.5332054
X-RAY DIFFRACTIONr_mcbond_other3.5084.5322053
X-RAY DIFFRACTIONr_mcangle_it4.8666.7772564
X-RAY DIFFRACTIONr_mcangle_other4.8656.7792565
X-RAY DIFFRACTIONr_scbond_it4.1634.9562095
X-RAY DIFFRACTIONr_scbond_other4.1644.9572094
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.3797.2333075
X-RAY DIFFRACTIONr_long_range_B_refined8.8285.95419082
X-RAY DIFFRACTIONr_long_range_B_other8.82185.94519072
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.319 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.327 195 -
Rwork0.28 3725 -
obs--99.87 %

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