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- PDB-4hw3: Discovery of potent Mcl-1 inhibitors using fragment-based methods... -

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Basic information

Entry
Database: PDB / ID: 4hw3
TitleDiscovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based design
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS/INHIBITOR / regulation of apoptosis / maintenance of viability / APOPTOSIS / APOPTOSIS-INHIBITOR complex
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 / protein transmembrane transporter activity / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand ...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 / protein transmembrane transporter activity / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / 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 / 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 / cytosol / cytoplasm
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
Chem-19G / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsZhao, 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
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
B: Induced myeloid leukemia cell differentiation protein Mcl-1
C: Induced myeloid leukemia cell differentiation protein Mcl-1
D: Induced myeloid leukemia cell differentiation protein Mcl-1
E: Induced myeloid leukemia cell differentiation protein Mcl-1
F: Induced myeloid leukemia cell differentiation protein Mcl-1
G: Induced myeloid leukemia cell differentiation protein Mcl-1
H: Induced myeloid leukemia cell differentiation protein Mcl-1
I: Induced myeloid leukemia cell differentiation protein Mcl-1
J: Induced myeloid leukemia cell differentiation protein Mcl-1
K: Induced myeloid leukemia cell differentiation protein Mcl-1
L: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)214,42524
Polymers209,92712
Non-polymers4,49912
Water4,522251
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
F: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
7
G: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
8
H: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
9
I: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
10
J: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
11
K: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
12
L: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8692
Polymers17,4941
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)139.446, 58.760, 140.675
Angle α, β, γ (deg.)90.00, 90.71, 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: 17493.906 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Plasmid: pDEST-HisMBP / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-CodonPlus (DE3)-RIL / References: UniProt: Q07820
#2: Chemical
ChemComp-19G / 3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-benzothiophene-2-carboxylic acid


Mass: 374.881 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C20H19ClO3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 251 / 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: 2.75 Å3/Da / Density % sol: 55.19 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 30% PEG3350, 0.2M MgCl2, pH 6.5, 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: 2.4→50 Å / % possible obs: 98.2 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 3.5 % / Rmerge(I) obs: 0.053 / Rsym value: 0.045 / Net I/σ(I): 23.7
Reflection shellResolution: 2.4→2.44 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.299 / Mean I/σ(I) obs: 2.55 / Num. unique all: 4328 / Rsym value: 0.364 / % possible all: 96.3

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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: 2.4→29.98 Å / SU ML: 0.33 / Isotropic thermal model: Anisotropic / σ(F): 1.46 / Phase error: 26.32 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2628 2001 2.26 %RANDOM
Rwork0.2151 ---
all0.2162 88515 --
obs0.2162 88346 98.23 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.4→29.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14358 0 300 251 14909
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0114919
X-RAY DIFFRACTIONf_angle_d1.41120092
X-RAY DIFFRACTIONf_dihedral_angle_d19.6125550
X-RAY DIFFRACTIONf_chiral_restr0.082193
X-RAY DIFFRACTIONf_plane_restr0.0082551
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.460.31311410.27155999X-RAY DIFFRACTION96
2.46-2.52650.351300.26855978X-RAY DIFFRACTION96
2.5265-2.60080.33731450.25975983X-RAY DIFFRACTION97
2.6008-2.68470.27731370.24886088X-RAY DIFFRACTION97
2.6847-2.78060.31741430.24676057X-RAY DIFFRACTION98
2.7806-2.89190.30961470.24466113X-RAY DIFFRACTION98
2.8919-3.02340.3071430.24616115X-RAY DIFFRACTION98
3.0234-3.18260.3011410.24276190X-RAY DIFFRACTION99
3.1826-3.38170.3161400.24046232X-RAY DIFFRACTION99
3.3817-3.64240.27241480.22716239X-RAY DIFFRACTION99
3.6424-4.00820.23691410.19756223X-RAY DIFFRACTION99
4.0082-4.58640.22371460.18826304X-RAY DIFFRACTION100
4.5864-5.77170.23561480.19896319X-RAY DIFFRACTION100
5.7717-29.98260.21561510.17796505X-RAY DIFFRACTION99

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