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- PDB-8t6f: Crystal structure of human MBP-Myeloid cell leukemia 1 (Mcl-1) in... -

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Basic information

Entry
Database: PDB / ID: 8t6f
TitleCrystal structure of human MBP-Myeloid cell leukemia 1 (Mcl-1) in complex with BRD810 inhibitor
ComponentsMaltose/maltodextrin-binding periplasmic protein/Induced myeloid leukemia cell differentiation protein Mcl-1 Chimera
KeywordsAPOPTOSIS / Inhibitor / MCL1 / MBP-fusion / BRD810
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 / detection of maltose stimulus / maltose transport complex / BH3 domain binding / carbohydrate transport ...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 / detection of maltose stimulus / maltose transport complex / BH3 domain binding / carbohydrate transport / carbohydrate transmembrane transporter activity / negative regulation of anoikis / maltose binding / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / maltose transport / maltodextrin transmembrane transport / protein transmembrane transporter activity / 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 / cell chemotaxis / release of cytochrome c from mitochondria / response to cytokine / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / outer membrane-bounded periplasmic space / regulation of apoptotic process / Interleukin-4 and Interleukin-13 signaling / mitochondrial outer membrane / periplasmic space / positive regulation of apoptotic process / protein heterodimerization activity / DNA damage response / negative regulation of apoptotic process / protein homodimerization activity / mitochondrion / nucleoplasm / membrane / nucleus / cytoplasm / cytosol
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
TRIETHYLENE GLYCOL / : / Maltose/maltodextrin-binding periplasmic protein / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesEscherichia coli K-12 (bacteria)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.56 Å
AuthorsPoncet-Montange, G. / Lemke, C.T.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: to be published
Title: BRD810 is a novel highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models
Authors: Rauh, U. / Wei, G. / Serrano-Wu, M. / Kosmidis, G. / Kaulfuss, S. / Siegel, F. / Thede, K. / McFarland, J. / Poncet-Montange, G. / Lemke, T.L. / Werbeck, N. / Nowak-Reppel, K. / Pilari, S. / ...Authors: Rauh, U. / Wei, G. / Serrano-Wu, M. / Kosmidis, G. / Kaulfuss, S. / Siegel, F. / Thede, K. / McFarland, J. / Poncet-Montange, G. / Lemke, T.L. / Werbeck, N. / Nowak-Reppel, K. / Pilari, S. / Menz, S. / Ocker, M. / Kaushik, V. / Hubbard, B. / Ziegelbauer, K. / Golub, T.R.
History
DepositionJun 15, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein/Induced myeloid leukemia cell differentiation protein Mcl-1 Chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,6096
Polymers57,3111
Non-polymers1,2985
Water7,296405
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)98.301, 136.957, 38.257
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein Maltose/maltodextrin-binding periplasmic protein/Induced myeloid leukemia cell differentiation protein Mcl-1 Chimera


Mass: 57310.883 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli K-12 (bacteria), (gene. exp.) Homo sapiens (human)
Gene: malE, b4034, JW3994, MCL1, BCL2L3 / Production host: Escherichia coli O157:H7 (bacteria) / References: UniProt: P0AEX9, UniProt: Q07820
#2: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose


Type: oligosaccharide / Mass: 342.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
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

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Non-polymers , 5 types, 409 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-YI7 / (3aM,9S,15R)-4-chloro-3-ethyl-7-{3-[(6-fluoronaphthalen-1-yl)oxy]propyl}-2-methyl-15-[2-(morpholin-4-yl)ethyl]-2,10,11,12,13,15-hexahydropyrazolo[4',3':9,10][1,6]oxazacycloundecino[8,7,6-hi]indole-8-carboxylic acid


Mass: 703.242 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H44ClFN4O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 405 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.25 Å3/Da / Density % sol: 45.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 3.75 mg/mL MBP-MCL1, 17.5 mM HEPES pH 7.5, 8% PEG 3350, 5% MPD, 5% DMSO, 2.5% PEG400, 75mM NaCl, 25mM Magnesium Formate, 0.75mM DTT, 0.75 mM Maltose, 0.5mM ANJ810, 0.375% glycerol, ~10-4 ...Details: 3.75 mg/mL MBP-MCL1, 17.5 mM HEPES pH 7.5, 8% PEG 3350, 5% MPD, 5% DMSO, 2.5% PEG400, 75mM NaCl, 25mM Magnesium Formate, 0.75mM DTT, 0.75 mM Maltose, 0.5mM ANJ810, 0.375% glycerol, ~10-4 diluted microseeds, equilibrated against 1.5M NaCl in a EasyXtal 15-Well DropGuard Crystallization Tool

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.97903 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Oct 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97903 Å / Relative weight: 1
ReflectionResolution: 1.56→80 Å / Num. obs: 74575 / % possible obs: 99.71 % / Redundancy: 7.1 % / Biso Wilson estimate: 25.74 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.037 / Rrim(I) all: 0.04 / Net I/σ(I): 20.5
Reflection shellResolution: 1.56→1.59 Å / Rmerge(I) obs: 0.663 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 3580 / CC1/2: 0.909 / % possible all: 97.3

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
DIALSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.56→79.86 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.54 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2181 3735 5.02 %
Rwork0.1883 --
obs0.1898 74453 99.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.56→79.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4042 0 88 405 4535
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006
X-RAY DIFFRACTIONf_angle_d0.878
X-RAY DIFFRACTIONf_dihedral_angle_d5.476618
X-RAY DIFFRACTIONf_chiral_restr0.053638
X-RAY DIFFRACTIONf_plane_restr0.007758
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.56-1.580.34411310.29822482X-RAY DIFFRACTION96
1.58-1.61742577X-RAY DIFFRACTION100
1.6-1.620.2591230.25492547X-RAY DIFFRACTION99
1.62-1.640.2911380.24852593X-RAY DIFFRACTION100
1.64-1.670.28311250.24662630X-RAY DIFFRACTION100
1.67-1.70.30051280.25862561X-RAY DIFFRACTION100
1.7-1.720.2951510.27282586X-RAY DIFFRACTION100
1.72-1.750.33811260.26922577X-RAY DIFFRACTION100
1.75-1.780.31881420.25332587X-RAY DIFFRACTION99
1.78-1.820.31651190.24732655X-RAY DIFFRACTION99
1.82-1.860.28011340.22982564X-RAY DIFFRACTION100
1.86-1.90.24791420.22222600X-RAY DIFFRACTION100
1.9-1.940.26491290.21562601X-RAY DIFFRACTION100
1.94-1.990.24741270.20882624X-RAY DIFFRACTION100
1.99-2.040.24811440.21022598X-RAY DIFFRACTION100
2.04-2.10.22911320.21962625X-RAY DIFFRACTION100
2.1-2.170.23741370.21442596X-RAY DIFFRACTION100
2.17-2.250.25591480.19792639X-RAY DIFFRACTION99
2.25-2.340.21751420.19032583X-RAY DIFFRACTION99
2.34-2.450.21021410.20132637X-RAY DIFFRACTION100
2.45-2.570.2441450.19532641X-RAY DIFFRACTION100
2.57-2.740.24141300.19122670X-RAY DIFFRACTION100
2.74-2.950.22371550.19752622X-RAY DIFFRACTION100
2.95-3.240.21071530.18662646X-RAY DIFFRACTION100
3.24-3.710.19331140.16772703X-RAY DIFFRACTION100
3.71-4.680.18521480.14152725X-RAY DIFFRACTION100
4.68-79.860.16161570.15892849X-RAY DIFFRACTION99

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