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- PDB-6vbx: Crystal structure of Mcl-1 in complex with 138E12 peptide, Lys-co... -

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Basic information

Entry
Database: PDB / ID: 6vbx
TitleCrystal structure of Mcl-1 in complex with 138E12 peptide, Lys-covalent antagonist
Components
  • Induced myeloid leukemia cell differentiation protein Mcl-1
  • Synthetic peptide
KeywordsAPOPTOSIS / MCL-1 / 138E12 peptide / Lys-covalent antagonists
Function / homology
Function and homology information


BIM-BCL-xl complex / BIM-BCL-2 complex / regulation of developmental pigmentation / RUNX3 regulates BCL2L11 (BIM) transcription / positive regulation of mitochondrial membrane permeability involved in apoptotic process / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / Activation of BIM and translocation to mitochondria / developmental pigmentation / positive regulation of fibroblast apoptotic process / apoptotic process involved in embryonic digit morphogenesis ...BIM-BCL-xl complex / BIM-BCL-2 complex / regulation of developmental pigmentation / RUNX3 regulates BCL2L11 (BIM) transcription / positive regulation of mitochondrial membrane permeability involved in apoptotic process / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / Activation of BIM and translocation to mitochondria / developmental pigmentation / positive regulation of fibroblast apoptotic process / apoptotic process involved in embryonic digit morphogenesis / ear development / positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / cell fate determination / meiosis I / positive regulation of T cell apoptotic process / regulation of organ growth / tube formation / mammary gland development / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / myeloid cell homeostasis / cellular response to glucocorticoid stimulus / NRAGE signals death through JNK / thymocyte apoptotic process / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / FOXO-mediated transcription of cell death genes / positive regulation of IRE1-mediated unfolded protein response / odontogenesis of dentin-containing tooth / positive regulation of release of cytochrome c from mitochondria / BH3 domain binding / T cell homeostasis / B cell homeostasis / negative regulation of anoikis / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of intrinsic apoptotic signaling pathway / spleen development / positive regulation of cell cycle / response to cytokine / extrinsic apoptotic signaling pathway in absence of ligand / endomembrane system / FLT3 Signaling / negative regulation of autophagy / response to endoplasmic reticulum stress / release of cytochrome c from mitochondria / thymus development / cell-matrix adhesion / post-embryonic development / kidney development / positive regulation of protein-containing complex assembly / male gonad development / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / Signaling by BRAF and RAF1 fusions / positive regulation of neuron apoptotic process / channel activity / Interleukin-4 and Interleukin-13 signaling / spermatogenesis / regulation of apoptotic process / microtubule binding / in utero embryonic development / mitochondrial outer membrane / positive regulation of apoptotic process / protein heterodimerization activity / apoptotic process / DNA damage response / protein kinase binding / negative regulation of apoptotic process / mitochondrion / nucleoplasm / nucleus / membrane / cytoplasm / cytosol
Similarity search - Function
Apoptosis, Bim N-terminal / Bcl-2-like protein 11 / : / Bim protein N-terminus / Bcl-x interacting, BH3 domain / Bcl-x interacting, BH3 domain / Apoptosis regulator, Mcl-1 / Blc2-like / Apoptosis Regulator Bcl-x / Apoptosis regulator, Bcl-2, BH3 motif, conserved site ...Apoptosis, Bim N-terminal / Bcl-2-like protein 11 / : / Bim protein N-terminus / Bcl-x interacting, BH3 domain / Bcl-x interacting, BH3 domain / 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-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like / Bcl-2, Bcl-2 homology region 1-3 / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Bcl-2-like protein 11 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsPellecchia, M. / Perry, J.J. / Kenjic, N. / Assar, Z.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA168517 United States
Citation
Journal: J.Med.Chem. / Year: 2021
Title: Design, Synthesis, and Structural Characterization of Lysine Covalent BH3 Peptides Targeting Mcl-1.
Authors: Gambini, L. / Udompholkul, P. / Baggio, C. / Muralidharan, A. / Kenjic, N. / Assar, Z. / Perry, J.J.P. / Pellecchia, M.
#1: Journal: Meth. Enzymol. / Year: 1997
Title: Processing of X-ray diffraction data collected in oscillation mode.
Authors: Otwinowski, Z. / Minor, W.
#2: Journal: J Appl Crystallogr / Year: 2007
Title: Phaser crystallographic software.
Authors: McCoy, A.J. / Grosse-Kunstleve, R.W. / Adams, P.D. / Winn, M.D. / Storoni, L.C. / Read, R.J.
#3: Journal: Acta Crystallogr. D Biol. Crystallogr. / Year: 2004
Title: REFMAC5 dictionary: organization of prior chemical knowledge and guidelines for its use.
Authors: Vagin, A.A. / Steiner, R.A. / Lebedev, A.A. / Potterton, L. / McNicholas, S. / Long, F. / Murshudov, G.N.
#4: Journal: Acta Crystallogr D Biol Crystallogr / Year: 2004
Title: Coot: model-building tools for molecular graphics.
Authors: Paul Emsley / Kevin Cowtan /
Abstract: CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality ...CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics. The map-fitting tools are available as a stand-alone package, distributed as 'Coot'.
History
DepositionDec 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 30, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 9, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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
Revision 1.2Oct 11, 2023Group: 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

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Assembly

Deposited unit
A: Induced myeloid leukemia cell differentiation protein Mcl-1
B: Synthetic peptide


Theoretical massNumber of molelcules
Total (without water)19,6552
Polymers19,6552
Non-polymers00
Water79344
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1460 Å2
ΔGint-11 kcal/mol
Surface area8440 Å2
MethodPISA
2
A: Induced myeloid leukemia cell differentiation protein Mcl-1
B: Synthetic peptide

A: Induced myeloid leukemia cell differentiation protein Mcl-1
B: Synthetic peptide


Theoretical massNumber of molelcules
Total (without water)39,3114
Polymers39,3114
Non-polymers00
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555y,x,-z1
Buried area4700 Å2
ΔGint-23 kcal/mol
Surface area15100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.607, 54.607, 97.838
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"

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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: 17850.330 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: Protein/peptide Synthetic peptide


Mass: 1805.020 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: This is a chemically synthesized peptide with unnatural ligand (see ligand section) on the N-terminal end. Ligands is covalently attached to Lys234 of chain A.
Source: (synth.) synthetic construct (others) / References: UniProt: O43521*PLUS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / 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: 43.55 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 0.5M Potassium Thiocyanate, 0.1M Sodium Acetate:HCL pH4.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.127 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Oct 31, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.127 Å / Relative weight: 1
ReflectionResolution: 1.95→34.001 Å / Num. obs: 12721 / % possible obs: 99.75 % / Redundancy: 7.9 % / Biso Wilson estimate: 32.63 Å2 / Rmerge(I) obs: 0.073 / Net I/σ(I): 22
Reflection shellResolution: 1.955→2.025 Å / Redundancy: 8.4 % / Rmerge(I) obs: 0.276 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 1235 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
Cootmodel building
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2NL9

2nl9


Resolution: 1.95→34 Å / SU ML: 0.2912 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 34.0423
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2779 601 4.72 %
Rwork0.2503 12120 -
obs0.2518 12721 99.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 35.58 Å2
Refinement stepCycle: LAST / Resolution: 1.95→34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1234 0 21 44 1299
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00671273
X-RAY DIFFRACTIONf_angle_d0.80691708
X-RAY DIFFRACTIONf_chiral_restr0.0536189
X-RAY DIFFRACTIONf_plane_restr0.004217
X-RAY DIFFRACTIONf_dihedral_angle_d10.0004753
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-2.150.35431340.27422992X-RAY DIFFRACTION100
2.15-2.460.32821320.27352965X-RAY DIFFRACTION99.2
2.46-3.10.31211340.26933038X-RAY DIFFRACTION99.97

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