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- PDB-6ua3: Human Mcl-1 in complex with a modified Bim BH3 peptide -

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Basic information

Entry
Database: PDB / ID: 6ua3
TitleHuman Mcl-1 in complex with a modified Bim BH3 peptide
Components
  • Induced myeloid leukemia cell differentiation protein Mcl-1
  • modified Bim BH3 peptide
KeywordsPEPTIDE BINDING PROTEIN/Inhibitor / Inhibitor / PEPTIDE BINDING PROTEIN / PEPTIDE BINDING PROTEIN-Inhibitor complex
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 / developmental pigmentation / Activation of BIM and translocation to mitochondria / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / 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 / developmental pigmentation / Activation of BIM and translocation to mitochondria / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / positive regulation of fibroblast apoptotic process / apoptotic process involved in embryonic digit morphogenesis / ear development / tube formation / meiosis I / positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / mammary gland development / cell fate determination / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / positive regulation of T cell apoptotic process / regulation of organ growth / cellular response to glucocorticoid stimulus / mitochondrial fusion / channel activity / Bcl-2 family protein complex / myeloid cell homeostasis / FOXO-mediated transcription of cell death genes / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / NRAGE signals death through JNK / thymocyte apoptotic process / T cell homeostasis / BH3 domain binding / odontogenesis of dentin-containing tooth / positive regulation of IRE1-mediated unfolded protein response / positive regulation of release of cytochrome c from mitochondria / B cell homeostasis / protein transmembrane transporter activity / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / endomembrane system / positive regulation of cell cycle / positive regulation of intrinsic apoptotic signaling pathway / extrinsic apoptotic signaling pathway in absence of ligand / spleen development / FLT3 Signaling / response to endoplasmic reticulum stress / cell-matrix adhesion / negative regulation of autophagy / post-embryonic development / release of cytochrome c from mitochondria / thymus development / kidney development / response to cytokine / positive regulation of protein-containing complex assembly / male gonad development / activation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of neuron apoptotic process / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by BRAF and RAF1 fusions / microtubule binding / spermatogenesis / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / in utero embryonic development / mitochondrial outer membrane / molecular adaptor activity / positive regulation of apoptotic process / protein heterodimerization activity / apoptotic process / DNA damage response / negative regulation of apoptotic process / protein kinase binding / protein homodimerization activity / mitochondrion / nucleoplasm / membrane / nucleus / cytosol / cytoplasm
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 / 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, 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 / 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
Bcl-2-like protein 11 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.552 Å
AuthorsMandal, T. / Grant, R.A. / Keating, A.E.
Funding support United States, 1items
OrganizationGrant numberCountry
Department of Defense (DOD, United States) United States
CitationJournal: To Be Published
Title: Inhibitor peptides against Mcl-1 containing non-natural amino acids show potent apoptotic response.
Authors: Mandal, T. / Grant, R.A. / Keating, A.E.
History
DepositionSep 10, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 16, 2020Provider: repository / Type: Initial release

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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: modified Bim BH3 peptide


Theoretical massNumber of molelcules
Total (without water)20,4402
Polymers20,4402
Non-polymers00
Water2,486138
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2260 Å2
ΔGint-19 kcal/mol
Surface area9110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)31.096, 56.408, 99.461
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 17823.258 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 modified Bim BH3 peptide


Mass: 2617.043 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: O43521*PLUS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 138 / 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: 2.21 Å3/Da / Density % sol: 44.35 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: 1.4 M Na Citrate pH 6.5 0.1 M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9791 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 12, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.55→100 Å / Num. obs: 24123 / % possible obs: 92.6 % / Redundancy: 9.6 % / Biso Wilson estimate: 21.28 Å2 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.024 / Rrim(I) all: 0.082 / Χ2: 1.085 / Net I/σ(I): 7.3 / Num. measured all: 231240
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.55-1.582.20.3826400.780.2520.4620.77351.2
1.58-1.612.80.3887980.7920.2260.4540.95662.3
1.61-1.643.30.3129000.8770.1680.3590.97870.8
1.64-1.673.80.3310240.8740.1670.3730.9580.3
1.67-1.714.80.33911430.8890.1610.3790.91688.9
1.71-1.755.90.34412450.8750.1540.380.95297.3
1.75-1.7980.34112760.9390.1310.3660.94999.5
1.79-1.848.80.34112930.9560.1230.3630.95699.9
1.84-1.899.70.32812690.9680.1110.3470.983100
1.89-1.9510.30.29512950.9630.0970.3111.06299.9
1.95-2.0210.20.25612750.9770.0840.271.12999.7
2.02-2.1120.21412970.9880.0640.2241.208100
2.1-2.212.50.18213010.9910.0530.191.211100
2.2-2.3212.30.15613000.9940.0450.1621.271100
2.32-2.4611.60.13513020.9930.0410.1421.27199.8
2.46-2.6513.10.11513050.9960.0330.1191.203100
2.65-2.9212.90.09613190.9970.0280.11.171100
2.92-3.3412.20.06813370.9980.020.0721.12499.9
3.34-4.2112.90.04913490.9990.0140.0511.01999.9
4.21-10011.60.03614550.9990.0110.0380.7299.5

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation4.68 Å49.73 Å
Translation4.68 Å49.73 Å

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHASER2.8.0phasing
PHENIXrefinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.552→49.73 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 20.19 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2035 1994 8.32 %
Rwork0.1711 21960 -
obs0.1738 23954 91.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 121.95 Å2 / Biso mean: 30.075 Å2 / Biso min: 12.9 Å2
Refinement stepCycle: final / Resolution: 1.552→49.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1435 0 0 138 1573
Biso mean---37.79 -
Num. residues----178
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0031465
X-RAY DIFFRACTIONf_angle_d0.5331971
X-RAY DIFFRACTIONf_chiral_restr0.038213
X-RAY DIFFRACTIONf_plane_restr0.003253
X-RAY DIFFRACTIONf_dihedral_angle_d14.139882
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.5521-1.59090.3176750.262482250
1.5909-1.6340.23921030.2265114267
1.634-1.6820.25271210.2071132880
1.682-1.73630.26271440.2079158293
1.7363-1.79840.20991500.1818164699
1.7984-1.87040.22251520.18151679100
1.8704-1.95550.2031540.179169999
1.9555-2.05860.23071520.1752166899
2.0586-2.18760.1961530.1642167999
2.1876-2.35650.18431550.16171706100
2.3565-2.59370.21891570.17061727100
2.5937-2.96890.19261530.1801171399
2.9689-3.74030.19061590.16871740100
3.7403-49.730.19791660.1573182998
Refinement TLS params.Method: refined / Origin x: 3.389 Å / Origin y: -6.7563 Å / Origin z: -14.1515 Å
111213212223313233
T0.1397 Å2-0.0098 Å2-0.0131 Å2-0.1472 Å20.0029 Å2--0.1429 Å2
L0.7236 °2-0.357 °20.2206 °2-0.9403 °2-0.2994 °2--0.9724 °2
S-0.0336 Å °0.0028 Å °-0.0104 Å °0.0404 Å °0.0027 Å °-0.0154 Å °-0.0877 Å °0.074 Å °0.0002 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA171 - 325
2X-RAY DIFFRACTION1allB3 - 25
3X-RAY DIFFRACTION1allS1 - 146

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