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- PDB-8av9: INDUCED MYELOID LEUKEMIA CELL DIFFERENTIATION PROTEIN FABCOMPLEX ... -

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Basic information

Entry
Database: PDB / ID: 8av9
TitleINDUCED MYELOID LEUKEMIA CELL DIFFERENTIATION PROTEIN FABCOMPLEX IN COMPLEX WITH COMPOUND 1
Components
  • Fab Heavy ChainFragment antigen-binding
  • Fab Light ChainFragment antigen-binding
  • Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / MCL1 / FAB / MACROCYCLE / MCL1-FAB_55_C6HIS / IMMUNE SYSTEM
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 / negative regulation of anoikis / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand ...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 / negative regulation of anoikis / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / 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 / 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
Similarity search - Domain/homology
Chem-VF8 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsHargreaves, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2023
Title: Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1.
Authors: Hargreaves, D. / Carbajo, R.J. / Bodnarchuk, M.S. / Embrey, K. / Rawlins, P.B. / Packer, M. / Degorce, S.L. / Hird, A.W. / Johannes, J.W. / Chiarparin, E. / Schade, M.
History
DepositionAug 26, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 24, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Induced myeloid leukemia cell differentiation protein Mcl-1
H: Fab Heavy Chain
L: Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,6484
Polymers68,0353
Non-polymers6131
Water6,017334
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5020 Å2
ΔGint-28 kcal/mol
Surface area25780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)149.284, 41.945, 106.071
Angle α, β, γ (deg.)90.000, 112.720, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Induced myeloid leukemia cell differentiation protein Mcl-1 / Bcl-2-like protein 3 / Bcl2-L-3 / Bcl-2-related protein EAT/mcl1 / mcl1/EAT


Mass: 18227.592 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Production host: Komagataella pastoris (fungus) / References: UniProt: Q07820
#2: Antibody Fab Heavy Chain / Fragment antigen-binding


Mass: 24488.490 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Komagataella pastoris (fungus)
#3: Antibody Fab Light Chain / Fragment antigen-binding


Mass: 25318.660 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Komagataella pastoris (fungus)
#4: Chemical ChemComp-VF8 / (3R,6R,7S,8E,11S,12R,22S)-6'-chloro-7-methoxy-11,12-dimethyl-13,13-dioxo-spiro[20-oxa-13-gamma6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene-22,1'-tetralin]-15-one


Mass: 613.207 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H41ClN2O5S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 334 / 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: 2.25 Å3/Da / Density % sol: 45.36 %
Crystal growTemperature: 310 K / Method: vapor diffusion / Details: 15% Peg2kMME, PCTP 0.1M pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 4, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.99→70.58 Å / Num. obs: 41926 / % possible obs: 99.7 % / Redundancy: 3.2 % / Biso Wilson estimate: 28.26 Å2 / Rmerge(I) obs: 0.079 / Net I/σ(I): 6.7
Reflection shellResolution: 1.99→2.04 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.577 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 41926 / % possible all: 99.7

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Processing

Software
NameVersionClassification
Aimlessdata scaling
BUSTER2.11.8 (24-FEB-2021)refinement
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in house

Resolution: 1.99→70.58 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.915 / SU R Cruickshank DPI: 0.206 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.212 / SU Rfree Blow DPI: 0.186 / SU Rfree Cruickshank DPI: 0.185
RfactorNum. reflection% reflectionSelection details
Rfree0.2724 2087 5.04 %RANDOM
Rwork0.2228 ---
obs0.2253 41416 98.3 %-
Displacement parametersBiso max: 102.16 Å2 / Biso mean: 36.79 Å2 / Biso min: 11.48 Å2
Baniso -1Baniso -2Baniso -3
1-4.9949 Å20 Å2-1.5939 Å2
2--4.1112 Å20 Å2
3----9.1061 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: final / Resolution: 1.99→70.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4390 0 42 334 4766
Biso mean--43.83 41.02 -
Num. residues----577
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1528SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes752HARMONIC5
X-RAY DIFFRACTIONt_it4535HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion602SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3829SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4535HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg6172HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion3.29
X-RAY DIFFRACTIONt_other_torsion18.2
LS refinement shellResolution: 1.99→2 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.436 40 4.83 %
Rwork0.367 789 -
all0.3703 829 -
obs--90.19 %

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