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- PDB-6ovc: hMcl1 inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 6ovc
TitlehMcl1 inhibitor complex
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS/INHIBITOR / inhibitor / Mcl1 small molecule complex / APOPTOSIS / 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 / 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 / response to cytokine / negative regulation of autophagy / release of cytochrome c from mitochondria / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / positive regulation of neuron apoptotic process / 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 / 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-N8J / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / simulated annealing
AuthorsPoppe, L.
CitationJournal: Cancer Discov / Year: 2018
Title: AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies.
Authors: Caenepeel, S. / Brown, S.P. / Belmontes, B. / Moody, G. / Keegan, K.S. / Chui, D. / Whittington, D.A. / Huang, X. / Poppe, L. / Cheng, A.C. / Cardozo, M. / Houze, J. / Li, Y. / Lucas, B. / ...Authors: Caenepeel, S. / Brown, S.P. / Belmontes, B. / Moody, G. / Keegan, K.S. / Chui, D. / Whittington, D.A. / Huang, X. / Poppe, L. / Cheng, A.C. / Cardozo, M. / Houze, J. / Li, Y. / Lucas, B. / Paras, N.A. / Wang, X. / Taygerly, J.P. / Vimolratana, M. / Zancanella, M. / Zhu, L. / Cajulis, E. / Osgood, T. / Sun, J. / Damon, L. / Egan, R.K. / Greninger, P. / McClanaghan, J.D. / Gong, J. / Moujalled, D. / Pomilio, G. / Beltran, P. / Benes, C.H. / Roberts, A.W. / Huang, D.C. / Wei, A. / Canon, J. / Coxon, A. / Hughes, P.E.
History
DepositionMay 7, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_nmr_spectrometer
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_nmr_spectrometer.model

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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)19,4122
Polymers18,8661
Non-polymers5451
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area8280 Å2
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)1 / 1structures with the lowest energy
RepresentativeModel #1lowest energy

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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: 18866.354 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 K-12 (bacteria) / References: UniProt: Q07820
#2: Chemical ChemComp-N8J / (2S)-N-(benzylsulfonyl)-4-(cyclobutylmethyl)-2-(2,4-dichlorophenyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxamide


Mass: 545.477 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H26Cl2N2O4S / Feature type: SUBJECT OF INVESTIGATION

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic12D X-filtered NOESY
121isotropic12D X filtered NOESY-HSQC
232isotropic12D HSQC-NOESY

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Sample preparation

Details
TypeSolution-IDContentsLabelSolvent system
solution10.5 mM [U-99% 13C; U-99% 15N] human Mcl1 protein, 0.5 mM small molecule, 20 mM sodium phosphate, 50 mM sodium chloride, 90% H2O/10% D2O1:1 complex90% H2O/10% D2O
solution20.5 mM [U-99% 13C; U-99% 15N] hMcl1 protein, 0.25 mg/L small molecule, 90% H2O/10% D2O2:1 complex90% H2O/10% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
0.5 mMhuman Mcl1 protein[U-99% 13C; U-99% 15N]1
0.5 mMsmall moleculenone1
20 mMsodium phosphatenone1
50 mMsodium chloridenone1
0.5 mMhMcl1 protein[U-99% 13C; U-99% 15N]2
0.25 mg/Lsmall moleculenone2
Sample conditions
Conditions-IDIonic strengthLabelpHPressure (kPa)Temperature (K)
150 mMconditions_17.41 atm298 K
250 mMconditions_27.41 atm310 K

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NMR measurement

NMR spectrometerType: Bruker AVANCE / Manufacturer: Bruker / Model: AVANCE / Field strength: 800 MHz

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Processing

NMR software
NameVersionDeveloperClassification
TopSpin3Bruker Biospindata analysis
MatlabMathWorks, Inc.structure calculation
MOECCGrefinement
RefinementMethod: simulated annealing / Software ordinal: 3
Details: The author states that the small molecule - protein complex was obtained by ligand-protein NOE constraints docking of a small molecule to a previously obtained NMR structure of the apo form (PDB entry 2MHS).
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 1 / Conformers submitted total number: 1

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