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- PDB-5vkc: Crystal structure of MCL-1 in complex with a BIM competitive inhibitor -

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Basic information

Entry
Database: PDB / ID: 5vkc
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
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / 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 ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / 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 / response to cytokine / release of cytochrome c from mitochondria / intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of neuron apoptotic process / Signaling by ALK fusions and activated point mutants / channel activity / 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 / mitochondrion / nucleoplasm / nucleus / membrane / 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-2 family ...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-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like / Bcl-2, Bcl-2 homology region 1-3 / 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-9EA / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.31 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
DepositionApr 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.type
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,94514
Polymers35,7652
Non-polymers2,18012
Water2,234124
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1440 Å2
ΔGint-229 kcal/mol
Surface area16330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.920, 63.920, 91.400
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number145
Space group name H-MP32

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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
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-9EA / 7-(3-{[4-(4-acetylpiperazin-1-yl)phenoxy]methyl}-1,5-dimethyl-1H-pyrazol-4-yl)-3-{3-[(naphthalen-1-yl)oxy]propyl}-1-[(pyridin-3-yl)methyl]-1H-indole-2-carboxylic acid


Mass: 762.895 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C46H46N6O5
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 124 / 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: 3.11 Å3/Da / Density % sol: 60.47 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 8.8
Details: 7%(w/v) PEG 8000, 0.1M Tris-HCl, pH 8.8, 0.2M zinc acetate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jun 13, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.3→500 Å / Num. obs: 18293 / % possible obs: 99.5 % / Redundancy: 4.9 % / Biso Wilson estimate: 46.53 Å2 / Rmerge(I) obs: 0.118 / Χ2: 1.368 / Net I/σ(I): 11.3 / Num. measured all: 89320
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsΧ2Diffraction-ID% possible all
2.3-2.382.30.4621.602197.1
2.38-2.483.10.4231.26198.7
2.48-2.5940.3881.449199.6
2.59-2.734.80.3411.2131100
2.73-2.95.40.2581.4161100
2.9-3.125.70.2041.3821100
3.12-3.445.80.1421.3341100
3.44-3.935.90.1121.3691100
3.93-4.965.90.0961.3371100
4.96-5005.80.081.431199.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
DENZOdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.31→22.81 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.928 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.267 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.255 / SU Rfree Blow DPI: 0.188 / SU Rfree Cruickshank DPI: 0.193
RfactorNum. reflection% reflectionSelection details
Rfree0.222 933 5.13 %RANDOM
Rwork0.201 ---
obs0.202 18180 99.4 %-
Displacement parametersBiso max: 148.89 Å2 / Biso mean: 49.95 Å2 / Biso min: 25.45 Å2
Baniso -1Baniso -2Baniso -3
1--3.5755 Å20 Å20 Å2
2---3.5755 Å20 Å2
3---7.1509 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: final / Resolution: 2.31→22.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2324 0 124 124 2572
Biso mean--41.09 55.52 -
Num. residues----288
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d898SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes58HARMONIC2
X-RAY DIFFRACTIONt_gen_planes418HARMONIC5
X-RAY DIFFRACTIONt_it2526HARMONIC20
X-RAY DIFFRACTIONt_nbd5SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion304SEMIHARMONIC5
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_contact2908SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2526HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3426HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion2.34
X-RAY DIFFRACTIONt_other_torsion20.45
LS refinement shellResolution: 2.31→2.45 Å / Rfactor Rfree error: 0 / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.237 141 4.88 %
Rwork0.215 2750 -
all0.216 2891 -
obs--97.34 %

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