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- PDB-8el1: Structure of MBP-Mcl-1 in complex with ABBV-467 -

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Basic information

Entry
Database: PDB / ID: 8el1
TitleStructure of MBP-Mcl-1 in complex with ABBV-467
ComponentsMaltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / MBP-Mcl-1 fusion protein / inhibitor complex / ABBV-467
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 transport complex / BH3 domain binding / maltose binding ...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 transport complex / BH3 domain binding / maltose binding / maltose transport / maltodextrin transmembrane transport / carbohydrate 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 / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / 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 / 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-WME / 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: 2.406 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 25, 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
B: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
C: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
D: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)242,06912
Polymers236,5484
Non-polymers5,5218
Water3,279182
1
A: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,5173
Polymers59,1371
Non-polymers1,3802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,5173
Polymers59,1371
Non-polymers1,3802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,5173
Polymers59,1371
Non-polymers1,3802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,5173
Polymers59,1371
Non-polymers1,3802
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)111.375, 79.617, 137.849
Angle α, β, γ (deg.)90, 90.22, 90
Int Tables number4
Space group name H-MP1211

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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.: 4 / 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.: 4 / 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-WME / (7R,16R)-19,23-dichloro-10-{[2-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic acid


Mass: 1037.976 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C53H51Cl2FN6O9S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 182 / 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: 2.58 Å3/Da / Density % sol: 52.39 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 25% (w/v) PEG 1500, 0.1 M MIB pH 6.0 (MIB is sodium malonate dibasic monohydrate, imidazole, boric acid)

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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: Dec 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.406→137.848 Å / Num. obs: 44489 / % possible obs: 87.9 % / Redundancy: 3.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.068 / Net I/σ(I): 10.3
Reflection shellResolution: 2.406→2.749 Å / Rmerge(I) obs: 0.522 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 2225 / CC1/2: 0.665

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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: 2.406→45.63 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.839 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.519 / Details: Used Global Phasing Staraniso data processing.
RfactorNum. reflection% reflectionSelection details
Rfree0.2907 2162 -RANDOM
Rwork0.1971 ---
obs0.2016 44481 47.3 %-
Displacement parametersBiso mean: 52.2 Å2
Baniso -1Baniso -2Baniso -3
1--0.2978 Å20 Å20.1329 Å2
2---1.5597 Å20 Å2
3---1.8576 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: LAST / Resolution: 2.406→45.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15474 0 380 183 16037
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00916244HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0122135HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5503SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes2968HARMONIC5
X-RAY DIFFRACTIONt_it16244HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion2148SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact13553SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.67
X-RAY DIFFRACTIONt_other_torsion21.61
LS refinement shellResolution: 2.41→2.61 Å
RfactorNum. reflection% reflection
Rfree0.329 44 -
Rwork0.2361 --
obs0.2403 890 4.45 %

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