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- PDB-6ybg: Structure of Mcl-1 in complex with compound 2g -

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Basic information

Entry
Database: PDB / ID: 6ybg
TitleStructure of Mcl-1 in complex with compound 2g
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / Apoptosis-inhibitor complex / Mcl-1 / S64315 / small molecule inhibitor
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / mitochondrial fusion / channel activity / 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 ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / mitochondrial fusion / channel activity / 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 / release of cytochrome c from mitochondria / response to cytokine / Signaling by ALK fusions and activated point mutants / 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 / 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 ...Apoptosis regulator, Mcl-1 / 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
Similarity search - Domain/homology
Chem-OJT / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsDokurno, P. / Surgenor, A.E. / Murray, J.B.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor.
Authors: Szlavik, Z. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Sipos, S. / Radics, G. / Proszenyak, A. / Balint, B. / Murray, J. / Davidson, J. / Chen, I. / Dokurno, P. / Surgenor, A.E. / Daniels, Z. ...Authors: Szlavik, Z. / Csekei, M. / Paczal, A. / Szabo, Z.B. / Sipos, S. / Radics, G. / Proszenyak, A. / Balint, B. / Murray, J. / Davidson, J. / Chen, I. / Dokurno, P. / Surgenor, A.E. / Daniels, Z.M. / Hubbard, R.E. / Le Toumelin-Braizat, G. / Claperon, A. / Lysiak-Auvity, G. / Girard, A.M. / Bruno, A. / Chanrion, M. / Colland, F. / Maragno, A.L. / Demarles, D. / Geneste, O. / Kotschy, A.
History
DepositionMar 17, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 2, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)40,4375
Polymers38,9862
Non-polymers1,4513
Water1,17165
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2363
Polymers19,4931
Non-polymers7432
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2012
Polymers19,4931
Non-polymers7081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)126.749, 79.061, 42.294
Angle α, β, γ (deg.)90.000, 98.860, 90.000
Int Tables number5
Space group name H-MC121

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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: 19493.154 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 BL21 (bacteria) / Variant (production host): pLysS / References: UniProt: Q07820
#2: Chemical ChemComp-OJT / (2~{R})-2-[5-[3-chloranyl-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(3-chlorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-(2-methoxyphenyl)propanoic acid


Mass: 707.666 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C36H36Cl2N4O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 65 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.1 Å3/Da / Density % sol: 59 %
Crystal growTemperature: 284 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M Hepes buffer pH 7.5, 0.2 M Ammonium Acetate, 30% PegMME550

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 14, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2→40 Å / Num. obs: 19966 / % possible obs: 71.7 % / Observed criterion σ(I): 1 / Redundancy: 4.1 % / Rmerge(I) obs: 0.076 / Χ2: 1.39 / Net I/σ(I): 18.6
Reflection shellResolution: 2→2.07 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.36 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 572 / Χ2: 1.3 / % possible all: 20.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6qz6

6qz6


Resolution: 2.1→20 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.941 / SU B: 5.192 / SU ML: 0.134 / SU R Cruickshank DPI: 0.2253 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.225 / ESU R Free: 0.2
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2353 885 4.6 %RANDOM
Rwork0.1803 ---
obs0.1828 18167 78.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 118.67 Å2 / Biso mean: 47.157 Å2 / Biso min: 26.18 Å2
Baniso -1Baniso -2Baniso -3
1--3.19 Å20 Å2-0.42 Å2
2--1.34 Å2-0 Å2
3---1.89 Å2
Refinement stepCycle: final / Resolution: 2.1→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2288 0 97 65 2450
Biso mean--46.43 52.78 -
Num. residues----287
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0132430
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172254
X-RAY DIFFRACTIONr_angle_refined_deg1.4761.6383281
X-RAY DIFFRACTIONr_angle_other_deg1.3711.5835174
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5475283
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.90120.857140
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.47915416
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8821524
X-RAY DIFFRACTIONr_chiral_restr0.0760.2309
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022699
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02561
LS refinement shellResolution: 2.1→2.212 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.317 61 -
Rwork0.252 1322 -
all-1383 -
obs--39.98 %

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