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- PDB-6zie: Crystal structure of MCL-1 in complex with a neutralizing Alphabo... -

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Basic information

Entry
Database: PDB / ID: 6zie
TitleCrystal structure of MCL-1 in complex with a neutralizing Alphabody CMPX-383B
Components
  • CMPX-383B
  • Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsANTITUMOR PROTEIN / de novo protein design / 3 helical antiparallel coiled coil / cell penetrating Alphabody MCL-1 neutralizing Alphabody
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 / 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
Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciessynthetic construct (others)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsPannecoucke, E. / Savvides, S.N. / Desmet, J. / Lasters, I.
Funding support Belgium, 1items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO) Belgium
CitationJournal: Sci Adv / Year: 2021
Title: Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting.
Authors: Pannecoucke, E. / Van Trimpont, M. / Desmet, J. / Pieters, T. / Reunes, L. / Demoen, L. / Vuylsteke, M. / Loverix, S. / Vandenbroucke, K. / Alard, P. / Henderikx, P. / Deroo, S. / Baatz, F. ...Authors: Pannecoucke, E. / Van Trimpont, M. / Desmet, J. / Pieters, T. / Reunes, L. / Demoen, L. / Vuylsteke, M. / Loverix, S. / Vandenbroucke, K. / Alard, P. / Henderikx, P. / Deroo, S. / Baatz, F. / Lorent, E. / Thiolloy, S. / Somers, K. / McGrath, Y. / Van Vlierberghe, P. / Lasters, I. / Savvides, S.N.
History
DepositionJun 25, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 28, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CMPX-383B
B: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6287
Polymers33,3012
Non-polymers3275
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2820 Å2
ΔGint-133 kcal/mol
Surface area13630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.699, 69.699, 261.289
Angle α, β, γ (deg.)90, 90, 120
Int Tables number178
Space group name H-MP6122
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+2/3
#8: -x,-y,z+1/2
#9: y,x,-z+1/3
#10: -y,-x,-z+5/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+1/6

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Components

#1: Protein CMPX-383B


Mass: 14950.066 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli BL21(DE3) (bacteria)
#2: 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: 18350.834 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 BL21(DE3) (bacteria) / References: UniProt: Q07820
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.75 Å3/Da / Density % sol: 58.17 %
Crystal growTemperature: 287 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 2% (w/v) PEG 3000 0.1 M sodium acetate pH 5.5 0.2 M zinc acetate dihydrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8729 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jun 9, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8729 Å / Relative weight: 1
ReflectionResolution: 2.3→44.33 Å / Num. obs: 17660 / % possible obs: 99.68 % / Redundancy: 8.9 % / Biso Wilson estimate: 55.8 Å2 / CC1/2: 1 / CC star: 1 / Rmerge(I) obs: 0.1112 / Rpim(I) all: 0.03928 / Rrim(I) all: 0.1181 / Net I/σ(I): 14.61
Reflection shellResolution: 2.301→2.383 Å / Redundancy: 8.8 % / Mean I/σ(I) obs: 0.85 / Num. unique obs: 1693 / CC1/2: 0.398 / CC star: 0.754 / % possible all: 97.31

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
MxCuBEdata collection
PHASERphasing
Coot0.9.4model building
PHENIXmodel building
XDSdata scaling
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MK8

3mk8


Resolution: 2.3→44.33 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.919 / SU R Cruickshank DPI: 0.274 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.287 / SU Rfree Blow DPI: 0.213 / SU Rfree Cruickshank DPI: 0.21
RfactorNum. reflection% reflectionSelection details
Rfree0.2592 1060 -RANDOM
Rwork0.24 ---
obs0.2412 17660 99.8 %-
Displacement parametersBiso mean: 80.46 Å2
Baniso -1Baniso -2Baniso -3
1--4.5365 Å20 Å20 Å2
2---4.5365 Å20 Å2
3---9.0731 Å2
Refine analyzeLuzzati coordinate error obs: 0.43 Å
Refinement stepCycle: LAST / Resolution: 2.3→44.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2151 0 5 31 2187
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0062187HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.82938HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d812SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes371HARMONIC5
X-RAY DIFFRACTIONt_it2187HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion308SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact1604SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.29
X-RAY DIFFRACTIONt_other_torsion17.16
LS refinement shellResolution: 2.3→2.32 Å
RfactorNum. reflection% reflection
Rfree0.1974 21 -
Rwork0.2604 --
obs0.2567 354 91.53 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
1-0.91960.6442-0.37034.01960.42492.18820.1251-0.2554-0.0347-0.2554-0.1114-0.0937-0.0347-0.0937-0.01370.17740.01770.0277-0.08320.0138-0.074517.91691.0832-14.2105
20.6202-0.11.15681.61570.07472.02530.110.0271-0.27780.0271-0.0346-0.2309-0.2778-0.2309-0.07540.22350.0220.0757-0.15290.0355-0.045320.257124.4409-4.0811
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|6 - A|144 }A6 - 144
2X-RAY DIFFRACTION2{ B|171 - B|322 }B171 - 322

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