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- PDB-6o6g: Co-crystal structure of Mcl1 with inhibitor -

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Basic information

Entry
Database: PDB / ID: 6o6g
TitleCo-crystal structure of Mcl1 with inhibitor
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS/INHIBITOR / apoptosis / inhibition / 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 / BH domain binding / 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 ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / BH domain binding / 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 / 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-LOJ / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsHuang, X.
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
DepositionMar 6, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 15, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2002
Polymers17,7931
Non-polymers4061
Water95553
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.610, 46.418, 45.072
Angle α, β, γ (deg.)90.00, 104.10, 90.00
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: 17793.229 Da / Num. of mol.: 1 / Fragment: residues 172-327
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-LOJ / (3S)-5-(cyclobutylmethyl)-3-(2,4-dichlorophenyl)-2,3,4,5-tetrahydro-1,5-benzoxazepine-7-carboxylic acid


Mass: 406.302 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21Cl2NO3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / 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: 2.3 Å3/Da / Density % sol: 46.48 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 100 mM Tris, pH 8.0, 3% Methanol, 30-42.5% PEG 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Sep 25, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 6445 / % possible obs: 88.5 % / Redundancy: 2.4 % / Net I/σ(I): 33.9
Reflection shellResolution: 2.3→2.38 Å / Num. unique obs: 363

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Processing

Software
NameClassification
CNXrefinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→27.8 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflectionSelection details
Rfree0.295 281 4.4 %RANDOM
Rwork0.29 ---
obs0.29 5978 92.9 %-
Refinement stepCycle: LAST / Resolution: 2.4→27.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1154 0 27 53 1234

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