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- PDB-4hw4: Discovery of potent Mcl-1 inhibitors using fragment-based methods... -

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Basic information

Entry
Database: PDB / ID: 4hw4
TitleDiscovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based design
Components
  • Induced myeloid leukemia cell differentiation protein Mcl-1
  • Mcl-1 BH3 peptide
KeywordsAPOPTOSIS / Anti-apoptotic protein / BH3 peptides
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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.53 Å
AuthorsFriberg, A. / Zhao, B.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design.
Authors: Friberg, A. / Vigil, D. / Zhao, B. / Daniels, R.N. / Burke, J.P. / Garcia-Barrantes, P.M. / Camper, D. / Chauder, B.A. / Lee, T. / Olejniczak, E.T. / Fesik, S.W.
History
DepositionNov 7, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 9, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2013Group: Database references

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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: Induced myeloid leukemia cell differentiation protein Mcl-1
C: Mcl-1 BH3 peptide
D: Mcl-1 BH3 peptide


Theoretical massNumber of molelcules
Total (without water)39,3994
Polymers39,3994
Non-polymers00
Water6,972387
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
C: Mcl-1 BH3 peptide


Theoretical massNumber of molelcules
Total (without water)19,6992
Polymers19,6992
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1830 Å2
ΔGint-13 kcal/mol
Surface area8650 Å2
MethodPISA
2
B: Induced myeloid leukemia cell differentiation protein Mcl-1
D: Mcl-1 BH3 peptide


Theoretical massNumber of molelcules
Total (without water)19,6992
Polymers19,6992
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1830 Å2
ΔGint-12 kcal/mol
Surface area7830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.070, 48.353, 68.183
Angle α, β, γ (deg.)90.00, 93.83, 90.00
Int Tables number4
Space group name H-MP1211

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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: 17850.281 Da / Num. of mol.: 2
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 Mcl-1 BH3 peptide


Mass: 1849.085 Da / Num. of mol.: 2 / Source method: obtained synthetically / Details: Synthetic peptide
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 387 / 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: 2.09 Å3/Da / Density % sol: 41.15 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 25% PEG3350, 0.2M NaCl, 0.1M Bis-Tris, pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Jun 19, 2012
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 1.53→50 Å / Num. all: 49398 / Num. obs: 49398 / % possible obs: 100 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Rmerge(I) obs: 0.047 / Rsym value: 0.042
Reflection shellResolution: 1.53→1.56 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.313 / Mean I/σ(I) obs: 2.46 / Num. unique all: 2464 / Rsym value: 0.408 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
PHENIX(phenix.refine: 1.8_1069)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.53→34.744 Å / SU ML: 0.14 / σ(F): 1.38 / Phase error: 19.41 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.184 2495 5.06 %RANDOM
Rwork0.1374 ---
all0.1398 49292 --
obs0.1398 49292 99.92 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.53→34.744 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2627 0 0 387 3014
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082697
X-RAY DIFFRACTIONf_angle_d1.0053621
X-RAY DIFFRACTIONf_dihedral_angle_d13.1751017
X-RAY DIFFRACTIONf_chiral_restr0.053404
X-RAY DIFFRACTIONf_plane_restr0.005467
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5298-1.55920.25241320.19422602X-RAY DIFFRACTION99
1.5592-1.59110.24711330.16942542X-RAY DIFFRACTION100
1.5911-1.62570.2341310.15272627X-RAY DIFFRACTION100
1.6257-1.66350.23281350.1492597X-RAY DIFFRACTION100
1.6635-1.70510.20381440.14182568X-RAY DIFFRACTION100
1.7051-1.75120.20511240.13722570X-RAY DIFFRACTION100
1.7512-1.80270.21881480.12882580X-RAY DIFFRACTION100
1.8027-1.86090.19541490.12622625X-RAY DIFFRACTION100
1.8609-1.92740.19491570.12592552X-RAY DIFFRACTION100
1.9274-2.00450.18331400.12462587X-RAY DIFFRACTION100
2.0045-2.09580.18931420.12182604X-RAY DIFFRACTION100
2.0958-2.20620.18881160.11292597X-RAY DIFFRACTION100
2.2062-2.34440.17541430.11772582X-RAY DIFFRACTION100
2.3444-2.52540.17541440.12682625X-RAY DIFFRACTION100
2.5254-2.77940.20161520.13022601X-RAY DIFFRACTION100
2.7794-3.18140.16861280.142614X-RAY DIFFRACTION100
3.1814-4.00730.16411330.13042640X-RAY DIFFRACTION100
4.0073-34.75340.16741440.16592684X-RAY DIFFRACTION99

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