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- PDB-6udv: X-ray co-crystal structure of compound 3 bound to human Mcl-1 -

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Basic information

Entry
Database: PDB / ID: 6udv
TitleX-ray co-crystal structure of compound 3 bound to human Mcl-1
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS/INHIBITOR / protein-protein interaction / apoptosis / inhibitor / 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-Q51 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsHuang, X. / Whittington, D.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an alpha-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.
Authors: Rescourio, G. / Gonzalez, A.Z. / Jabri, S. / Belmontes, B. / Moody, G. / Whittington, D. / Huang, X. / Caenepeel, S. / Cardozo, M. / Cheng, A.C. / Chow, D. / Dou, H. / Jones, A. / Kelly, R.C. ...Authors: Rescourio, G. / Gonzalez, A.Z. / Jabri, S. / Belmontes, B. / Moody, G. / Whittington, D. / Huang, X. / Caenepeel, S. / Cardozo, M. / Cheng, A.C. / Chow, D. / Dou, H. / Jones, A. / Kelly, R.C. / Li, Y. / Lizarzaburu, M. / Lo, M.C. / Mallari, R. / Meleza, C. / Rew, Y. / Simonovich, S. / Sun, D. / Turcotte, S. / Yan, X. / Wong, S.G. / Yanez, E. / Zancanella, M. / Houze, J. / Medina, J.C. / Hughes, P.E. / Brown, S.P.
History
DepositionSep 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2019Group: 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 1.2Mar 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5222
Polymers17,9221
Non-polymers5991
Water2,810156
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area8840 Å2
2
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules

A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,0434
Polymers35,8452
Non-polymers1,1982
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_557-x,y,-z+5/21
Buried area2080 Å2
ΔGint-11 kcal/mol
Surface area15600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.584, 89.370, 84.952
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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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: 17922.344 Da / Num. of mol.: 1
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-Q51 / (4S,7aR,9aR,10S,11E,14S,15R)-6'-chloro-10-hydroxy-14,15-dimethyl-3',4',7a,8,9,9a,10,13,14,15-decahydro-2'H,3H,5H-spiro[1,19-(ethanediylidene)-16lambda~6~-cyclobuta[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecine-4,1'-naphthalene]-16,16,18(7H,17H)-trione


Mass: 599.180 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H39ClN2O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 156 / 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: 2.33 Å3/Da / Density % sol: 47.26 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 0.1 M Tris pH 8.0, 3% eEthanol, 36% PEG6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 24, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.35→50 Å / Num. obs: 36627 / % possible obs: 99.9 % / Redundancy: 6.02 % / Rmerge(I) obs: 0.059 / Net I/σ(I): 11
Reflection shellResolution: 1.35→1.4 Å / Rmerge(I) obs: 0.845 / Num. unique obs: 3605

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
PDB_EXTRACT3.25data extraction
DENZOdata reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.35→44.69 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.948 / SU B: 0.979 / SU ML: 0.041 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.063 / ESU R Free: 0.067
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2404 1894 5.2 %RANDOM
Rwork0.2043 ---
obs0.206 34694 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 60.97 Å2 / Biso mean: 19.18 Å2 / Biso min: 9.72 Å2
Baniso -1Baniso -2Baniso -3
1-0.11 Å20 Å20 Å2
2--0.71 Å20 Å2
3----0.82 Å2
Refinement stepCycle: final / Resolution: 1.35→44.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1242 0 41 156 1439
Biso mean--15.08 33.83 -
Num. residues----155
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.021308
X-RAY DIFFRACTIONr_bond_other_d0.0010.02922
X-RAY DIFFRACTIONr_angle_refined_deg1.231.9841767
X-RAY DIFFRACTIONr_angle_other_deg0.8183.0052179
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.2925154
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.52522.90362
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.56515236
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.0461514
X-RAY DIFFRACTIONr_chiral_restr0.0940.2197
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021424
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02278
LS refinement shellResolution: 1.352→1.387 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.321 138 -
Rwork0.299 2346 -
all-2484 -
obs--98.53 %

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