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- PDB-6udy: X-ray co-crystal structure of compound 5 with Mcl-1 -

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Basic information

Entry
Database: PDB / ID: 6udy
TitleX-ray co-crystal structure of compound 5 with 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 / cell fate determination / cellular homeostasis / Bcl-2 family protein complex / mitochondrial fusion / 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 ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / Bcl-2 family protein complex / mitochondrial fusion / 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 / release of cytochrome c from mitochondria / negative regulation of autophagy / response to cytokine / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / channel activity / 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-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 / BCL2-like apoptosis inhibitors family profile. / Apoptosis regulator proteins, Bcl-2 family / Bcl-2-like superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-Q54 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsHuang, X.
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 11, 2019Provider: 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)36,6694
Polymers35,8452
Non-polymers8242
Water7,512417
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,3342
Polymers17,9221
Non-polymers4121
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)18,3342
Polymers17,9221
Non-polymers4121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.271, 84.954, 90.328
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-like protein 3 / Bcl2-L-3 / Bcl-2-related protein EAT/mcl1 / mcl1/EAT


Mass: 17922.344 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-Q54 / (3S)-6'-chloro-5-(cyclobutylmethyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[1,5-benzoxazepine-3,1'-naphthalene]-7-carboxylic acid


Mass: 411.921 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H26ClNO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 417 / 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: 2.42 Å3/Da / Density % sol: 49.07 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 0.1 M Tris pH 8.0, 3% Ethanol, 36% PEG6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Sep 7, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.7→500 Å / Num. obs: 35553 / % possible obs: 95 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.038 / Net I/σ(I): 19.1
Reflection shellResolution: 1.7→1.76 Å / Rmerge(I) obs: 0.385 / Num. unique obs: 2436

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Processing

Software
NameVersionClassification
CNSrefinement
PDB_EXTRACT3.25data extraction
DENZOdata reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→500 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflection
Rfree0.285 1778 4.8 %
Rwork0.2497 --
obs-35506 94.9 %
Displacement parametersBiso max: 61.39 Å2 / Biso mean: 25.4027 Å2 / Biso min: 11.5 Å2
Baniso -1Baniso -2Baniso -3
1--3.968 Å20 Å20 Å2
2--3.214 Å20 Å2
3---0.754 Å2
Refinement stepCycle: final / Resolution: 1.7→500 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2417 0 475 0 2892
Biso mean--34.97 --
Num. residues----301
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it0.8841.5
X-RAY DIFFRACTIONc_scbond_it1.562
X-RAY DIFFRACTIONc_mcangle_it1.392
X-RAY DIFFRACTIONc_scangle_it2.4182.5
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1mcl1.param
X-RAY DIFFRACTION22661685.xprm
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.param

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