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- PDB-8el0: Structure of MBP-Mcl-1 in complex with a macrocyclic compound -

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Basic information

Entry
Database: PDB / ID: 8el0
TitleStructure of MBP-Mcl-1 in complex with a macrocyclic compound
ComponentsMaltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / MBP-Mcl-1 fusion protein / inhibitor complex
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 / detection of maltose stimulus / maltose binding / maltose transport complex / maltose 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 / detection of maltose stimulus / maltose binding / maltose transport complex / maltose transport / maltodextrin transmembrane transport / BH3 domain binding / protein transmembrane transporter activity / carbohydrate transmembrane transporter activity / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / negative regulation of anoikis / carbohydrate transport / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / extrinsic apoptotic signaling pathway in absence of ligand / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / 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 / 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 / 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
Chem-WLW / 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: 1.917 Å
AuthorsJudge, R.A. / Judd, A.S. / Souers, A.J.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: Commun Med (Lond) / Year: 2023
Title: Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.
Authors: Yuda, J. / Will, C. / Phillips, D.C. / Abraham, L. / Alvey, C. / Avigdor, A. / Buck, W. / Besenhofer, L. / Boghaert, E. / Cheng, D. / Cojocari, D. / Doyle, K. / Hansen, T.M. / Huang, K. / ...Authors: Yuda, J. / Will, C. / Phillips, D.C. / Abraham, L. / Alvey, C. / Avigdor, A. / Buck, W. / Besenhofer, L. / Boghaert, E. / Cheng, D. / Cojocari, D. / Doyle, K. / Hansen, T.M. / Huang, K. / Johnson, E.F. / Judd, A.S. / Judge, R.A. / Kalvass, J.C. / Kunzer, A. / Lam, L.T. / Li, R. / Martin, R.L. / Mastracchio, A. / Mitten, M. / Petrich, A. / Wang, J. / Ward, J.E. / Zhang, H. / Wang, X. / Wolff, J.E. / Bell-McGuinn, K.M. / Souers, A.J.
History
DepositionSep 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 4, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name

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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)60,3803
Polymers59,1371
Non-polymers1,2432
Water7,044391
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)97.99, 136.943, 38.387
Angle α, β, γ (deg.)90, 90, 90
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: 59136.883 Da / Num. of mol.: 1 / Mutation: K194A,K197A,R201A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Strain: K12 / Gene: malE, b4034, JW3994, MCL1, BCL2L3 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): T1R / 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 natural 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
#3: Chemical ChemComp-WLW / (7R,20P)-18-chloro-1-(4-fluorophenyl)-10-{[(2M)-2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-19-methyl-15-[2-(4-methylpiperazin-1-yl)ethyl]-7,8,15,16-tetrahydro-14H-17,20-etheno-9,13-(metheno)-6-oxa-2-thia-3,5,15-triazacyclooctadeca[1,2,3-cd]indene-7-carboxylic acid


Mass: 900.458 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C49H47ClFN7O5S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 391 / Source method: isolated from a natural source / Formula: H2O
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: 2.18 Å3/Da / Density % sol: 43.52 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 26% (w/v) PEG 3350, 0.05 M magnesium formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 30, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.917→79.69 Å / Num. obs: 40544 / % possible obs: 99.9 % / Redundancy: 5.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Net I/σ(I): 17.5
Reflection shellResolution: 1.917→1.95 Å / Rmerge(I) obs: 0.903 / Mean I/σ(I) obs: 2 / Num. unique obs: 1953 / CC1/2: 0.726

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Processing

Software
NameVersionClassification
autoPROC1.1.7data processing
MOLREP11.9.02phasing
BUSTER2.11.8refinement
Coot0.8.9.2model building
XDS20210205data reduction
Aimless0.7.7data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WMS

4wms


Resolution: 1.917→79.69 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.945 / SU R Cruickshank DPI: 0.165 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.177 / SU Rfree Blow DPI: 0.147 / SU Rfree Cruickshank DPI: 0.143
RfactorNum. reflection% reflectionSelection details
Rfree0.2242 2055 -RANDOM
Rwork0.193 ---
obs0.1945 40543 99.8 %-
Displacement parametersBiso mean: 37.96 Å2
Baniso -1Baniso -2Baniso -3
1--2.5761 Å20 Å20 Å2
2--5.2806 Å20 Å2
3----2.7045 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 1.917→79.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4020 0 87 391 4498
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084206HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.865708HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1460SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes758HARMONIC5
X-RAY DIFFRACTIONt_it4206HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion546SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3940SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.05
X-RAY DIFFRACTIONt_other_torsion15.67
LS refinement shellResolution: 1.92→1.93 Å
RfactorNum. reflection% reflection
Rfree0.3052 49 -
Rwork0.2609 --
obs0.2635 811 97.23 %

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