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- PDB-6fs0: INDUCED MYELOID LEUKEMIA CELL DIFFERENTIATION PROTEIN FABCOMPLEX ... -

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Basic information

Entry
Database: PDB / ID: 6fs0
TitleINDUCED MYELOID LEUKEMIA CELL DIFFERENTIATION PROTEIN FABCOMPLEX IN COMPLEX WITH AZD5991
Components
  • Fab Heavy Chain
  • Fab Light Chain
  • Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / MCL1-FAB4460.55
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 / BH3 domain binding / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity ...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 / BH3 domain binding / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of autophagy / 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 / 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 / cytoplasm / cytosol
Similarity search - Function
Apoptosis regulator, Mcl-1 / Blc2-like / Apoptosis Regulator Bcl-x / 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 ...Apoptosis regulator, Mcl-1 / Blc2-like / Apoptosis Regulator Bcl-x / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
AZD5991 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsHargreaves, D.
CitationJournal: Nat Commun / Year: 2018
Title: Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia.
Authors: Tron, A.E. / Belmonte, M.A. / Adam, A. / Aquila, B.M. / Boise, L.H. / Chiarparin, E. / Cidado, J. / Embrey, K.J. / Gangl, E. / Gibbons, F.D. / Gregory, G.P. / Hargreaves, D. / Hendricks, J.A. ...Authors: Tron, A.E. / Belmonte, M.A. / Adam, A. / Aquila, B.M. / Boise, L.H. / Chiarparin, E. / Cidado, J. / Embrey, K.J. / Gangl, E. / Gibbons, F.D. / Gregory, G.P. / Hargreaves, D. / Hendricks, J.A. / Johannes, J.W. / Johnstone, R.W. / Kazmirski, S.L. / Kettle, J.G. / Lamb, M.L. / Matulis, S.M. / Nooka, A.K. / Packer, M.J. / Peng, B. / Rawlins, P.B. / Robbins, D.W. / Schuller, A.G. / Su, N. / Yang, W. / Ye, Q. / Zheng, X. / Secrist, J.P. / Clark, E.A. / Wilson, D.M. / Fawell, S.E. / Hird, A.W.
History
DepositionFeb 18, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 26, 2018Provider: repository / Type: Initial release

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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)64,5034
Polymers63,8303
Non-polymers6721
Water2,864159
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4950 Å2
ΔGint-29 kcal/mol
Surface area25830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)147.200, 42.050, 107.290
Angle α, β, γ (deg.)90.00, 113.17, 90.00
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: 17984.375 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07820
#2: Antibody Fab Heavy Chain


Mass: 22945.887 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Antibody Fab Light Chain


Mass: 22900.178 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#4: Chemical ChemComp-E4W / AZD5991


Mass: 672.259 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H34ClN5O3S2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 159 / 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: 2.39 Å3/Da / Density % sol: 48.58 % / Description: thin small plates
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.6
Details: 0.1M sodium acetate-HCL pH 4.6 18%W/V PEG-8000 0.2M calcium acetate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97858 Å
DetectorType: DECTRIS PILATUS3 X 1M / Detector: PIXEL / Date: Apr 10, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97858 Å / Relative weight: 1
ReflectionResolution: 2.24→49.32 Å / Num. obs: 29214 / % possible obs: 99.4 % / Redundancy: 3.7 % / Biso Wilson estimate: 42.36 Å2 / Net I/σ(I): 9
Reflection shellResolution: 2.24→2.32 Å

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.6refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→28.15 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.916 / Rfactor Rfree error: 0.03 / SU R Cruickshank DPI: 0.283 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.282 / SU Rfree Blow DPI: 0.205 / SU Rfree Cruickshank DPI: 0.208
RfactorNum. reflection% reflectionSelection details
Rfree0.233 1438 4.93 %RANDOM
Rwork0.193 ---
obs0.195 29147 100 %-
Displacement parametersBiso mean: 37.52 Å2
Baniso -1Baniso -2Baniso -3
1-3.8824 Å20 Å23.517 Å2
2--3.352 Å20 Å2
3----7.2344 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: LAST / Resolution: 2.25→28.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4386 0 46 159 4591
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014537HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.156175HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1510SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes92HARMONIC2
X-RAY DIFFRACTIONt_gen_planes661HARMONIC5
X-RAY DIFFRACTIONt_it4537HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.39
X-RAY DIFFRACTIONt_other_torsion18.05
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion594SEMIHARMONIC5
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_contact5122SEMIHARMONIC4
LS refinement shellResolution: 2.25→2.33 Å / Rfactor Rfree error: 0 / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.274 151 5.36 %
Rwork0.236 2664 -
all0.238 2815 -
obs--99.82 %

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