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- PDB-3mk8: The MCL-1 BH3 Helix is an Exclusive MCL-1 Inhibitor and Apoptosis... -

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Basic information

Entry
Database: PDB / ID: 3mk8
TitleThe MCL-1 BH3 Helix is an Exclusive MCL-1 Inhibitor and Apoptosis Sensitizer
Components(Induced myeloid leukemia cell differentiation protein Mcl-1) x 2
KeywordsAPOPTOSIS/APOPTOSIS REGULATOR / MCL-1 / MCL-1 SAHB D / staple / SAHB / BCL-2 family / apoptosis / anti-apoptotic / APOPTOSIS-APOPTOSIS REGULATOR complex
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH domain binding / BH3 domain binding / negative regulation of anoikis / protein transmembrane transporter activity ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH domain binding / BH3 domain binding / negative regulation of anoikis / protein transmembrane transporter activity / 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 / Signaling by ALK fusions and activated point mutants / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / mitochondrial outer membrane / positive regulation of apoptotic process / protein heterodimerization activity / DNA damage response / negative regulation of apoptotic process / 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
Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.321 Å
AuthorsStewart, M. / Fire, E. / Keating, A.E. / Walensky, L.D.
CitationJournal: Nat.Chem.Biol. / Year: 2010
Title: The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer.
Authors: Stewart, M.L. / Fire, E. / Keating, A.E. / Walensky, L.D.
History
DepositionApr 14, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 23, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software
Revision 1.3Oct 6, 2021Group: Database references / Derived calculations / Category: database_2 / struct_conn / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details
Revision 1.4Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.5Nov 22, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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


Theoretical massNumber of molelcules
Total (without water)20,3372
Polymers20,3372
Non-polymers00
Water1,26170
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1530 Å2
ΔGint-13 kcal/mol
Surface area8400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.505, 56.866, 63.984
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-related protein EAT/mcl1 / mcl1/EAT / Bcl-2-like protein 3 / Bcl2-L-3


Mass: 17937.359 Da / Num. of mol.: 1 / Fragment: MCL-1, residues 172-327
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2L3, MCL-1, MCL1 / Plasmid: pGEX / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q07820
#2: Protein/peptide Induced myeloid leukemia cell differentiation protein Mcl-1 / Bcl-2-related protein EAT/mcl1 / mcl1/EAT / Bcl-2-like protein 3 / Bcl2-L-3


Mass: 2399.813 Da / Num. of mol.: 1 / Fragment: MCL-1, residues 208-228 / Source method: obtained synthetically / References: UniProt: Q07820
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 70 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsAUTHOR STATES THAT THE BRIDGE OF TWO MK8 IS FORMED BY A DOUBLE BOND

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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: 1.99 Å3/Da / Density % sol: 38.21 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: PEG MME 2000, pH 6.5, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 1.5418 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 1, 2008
RadiationMonochromator: Crystal / Protocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.32→50 Å / Num. all: 7460 / Num. obs: 7405 / % possible obs: 99.3 % / Redundancy: 7 % / Biso Wilson estimate: 61.4 Å2 / Rsym value: 0.048 / Χ2: 1.344 / Net I/σ(I): 13.6
Reflection shellResolution: 2.32→2.4 Å / Redundancy: 6.8 % / Mean I/σ(I) obs: 4.8 / Num. unique all: 730 / Rsym value: 0.384 / Χ2: 0.579 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Chain A (MCL-1) of 3KJ0

3kj0


Resolution: 2.321→42.505 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.48 / σ(F): 1.36 / Stereochemistry target values: ML / Details: Used TLS refinement.
RfactorNum. reflection% reflectionSelection details
Rfree0.275 338 4.59 %Random
Rwork0.231 ---
obs0.233 7370 99.11 %-
all-7460 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 126.643 Å2 / ksol: 0.333 e/Å3
Displacement parametersBiso max: 222.53 Å2 / Biso mean: 86.236 Å2 / Biso min: 29.76 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.321→42.505 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1281 0 0 70 1351
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0021300
X-RAY DIFFRACTIONf_angle_d0.5911749
X-RAY DIFFRACTIONf_chiral_restr0.039196
X-RAY DIFFRACTIONf_plane_restr0.001222
X-RAY DIFFRACTIONf_dihedral_angle_d13.149483
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 2

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection allNum. reflection obs% reflection obs (%)
2.321-2.420.3421730.273346336363463100
2.924-42.5120.2571650.21635693734357099
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)
18.2003-1.5783-2.86625.05251.003710.8354-0.50540.14580.07110.42730.27120.32510.32850.26510.2410.24660.01980.00080.23640.02890.2119-0.9009-0.52655.5716
21.89390.8098-0.90191.8089-1.2724.4399-0.1867-1.2008-0.09080.04-0.5233-0.67040.56831.18810.74190.30780.1393-0.01191.3822-0.0340.490911.2759-0.9951-2.6372
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1Chain AA172 - 320
2X-RAY DIFFRACTION2Chain BB5 - 23

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