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- PDB-6b4l: Crystal structure of MCL-1 in complex with a BIM competitive inhibitor -

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Basic information

Entry
Database: PDB / ID: 6b4l
TitleCrystal structure of MCL-1 in complex with a BIM competitive inhibitor
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
Keywordssignaling protein/inhibitor / MCL-1 / signaling protein-inhibitor complex / SIGNALING PROTEIN
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 / 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 / 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-CJY / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsJudge, R.A. / Souers, A.J.
CitationJournal: J. Med. Chem. / Year: 2015
Title: Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity.
Authors: Bruncko, M. / Wang, L. / Sheppard, G.S. / Phillips, D.C. / Tahir, S.K. / Xue, J. / Erickson, S. / Fidanze, S. / Fry, E. / Hasvold, L. / Jenkins, G.J. / Jin, S. / Judge, R.A. / Kovar, P.J. / ...Authors: Bruncko, M. / Wang, L. / Sheppard, G.S. / Phillips, D.C. / Tahir, S.K. / Xue, J. / Erickson, S. / Fidanze, S. / Fry, E. / Hasvold, L. / Jenkins, G.J. / Jin, S. / Judge, R.A. / Kovar, P.J. / Madar, D. / Nimmer, P. / Park, C. / Petros, A.M. / Rosenberg, S.H. / Smith, M.L. / Song, X. / Sun, C. / Tao, Z.F. / Wang, X. / Xiao, Y. / Zhang, H. / Tse, C. / Leverson, J.D. / Elmore, S.W. / Souers, A.J.
History
DepositionSep 26, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 4, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4564
Polymers35,7652
Non-polymers6912
Water1,69394
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2282
Polymers17,8821
Non-polymers3451
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)18,2282
Polymers17,8821
Non-polymers3451
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.890, 82.929, 48.000
Angle α, β, γ (deg.)90.000, 117.500, 90.000
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: 17882.391 Da / Num. of mol.: 2 / Fragment: unp residues 174-326
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: Chemical ChemComp-CJY / 3-{3-[(naphthalen-1-yl)oxy]propyl}-1H-indole-2-carboxylic acid


Mass: 345.391 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H19NO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 2.41 Å3/Da / Density % sol: 48.94 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 9.5
Details: 18%(w/v)PEG 8000, 0.1M CHES pH 9.5, 4%(v/v) 2,2,2 trifluoroethanol
PH range: 7.5 - 9.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: May 14, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. obs: 12459 / % possible obs: 79.7 % / Redundancy: 3.2 % / Biso Wilson estimate: 36.23 Å2 / Rmerge(I) obs: 0.062 / Χ2: 1.114 / Net I/σ(I): 12.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.25-2.331.40.2182911.284118.9
2.33-2.421.60.2136281.169140.7
2.42-2.532.20.22610201.472164.8
2.53-2.672.80.19612731.352182.1
2.67-2.833.10.16314731.319194.5
2.83-3.053.50.12815211.061197.8
3.05-3.363.70.08815391.029198.5
3.36-3.853.70.0615591.011199.2
3.85-4.853.70.04315640.993199.3
4.85-503.50.04215911.078199.3

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
BUSTER2.11.4refinement
PDB_EXTRACT3.22data extraction
DENZOdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→42.58 Å / Cor.coef. Fo:Fc: 0.9054 / Cor.coef. Fo:Fc free: 0.8993 / SU R Cruickshank DPI: 0.584 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.547 / SU Rfree Blow DPI: 0.277 / SU Rfree Cruickshank DPI: 0.283
RfactorNum. reflection% reflectionSelection details
Rfree0.2582 628 5.05 %RANDOM
Rwork0.2183 ---
obs0.2203 12427 80.05 %-
Displacement parametersBiso max: 134.92 Å2 / Biso mean: 43.5 Å2 / Biso min: 16.57 Å2
Baniso -1Baniso -2Baniso -3
1--1.6063 Å20 Å23.3618 Å2
2--4.2953 Å20 Å2
3----2.6889 Å2
Refine analyzeLuzzati coordinate error obs: 0.329 Å
Refinement stepCycle: final / Resolution: 2.25→42.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2412 0 52 94 2558
Biso mean--36.11 44.15 -
Num. residues----300
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d916SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes58HARMONIC2
X-RAY DIFFRACTIONt_gen_planes392HARMONIC5
X-RAY DIFFRACTIONt_it2536HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion316SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2997SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2536HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3424HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion2.4
X-RAY DIFFRACTIONt_other_torsion20.07
LS refinement shellResolution: 2.25→2.46 Å / Rfactor Rfree error: 0 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2873 62 4.74 %
Rwork0.2299 1246 -
all0.2327 1308 -
obs--80.05 %

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