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- PDB-5fc4: Mcl-1 complexed with small molecule inhibitor -

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Basic information

Entry
Database: PDB / ID: 5fc4
TitleMcl-1 complexed with small molecule inhibitor
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
Keywordsapoptosis/apoptosis inhibitor / Mcl-1 / inhibitor / apoptosis-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 / mitochondrial fusion / channel activity / 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 / mitochondrial fusion / channel activity / 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 / 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 / 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-5WK / Chem-5WL / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsZhao, B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.
Authors: Pelz, N.F. / Bian, Z. / Zhao, B. / Shaw, S. / Tarr, J.C. / Belmar, J. / Gregg, C. / Camper, D.V. / Goodwin, C.M. / Arnold, A.L. / Sensintaffar, J.L. / Friberg, A. / Rossanese, O.W. / Lee, T. ...Authors: Pelz, N.F. / Bian, Z. / Zhao, B. / Shaw, S. / Tarr, J.C. / Belmar, J. / Gregg, C. / Camper, D.V. / Goodwin, C.M. / Arnold, A.L. / Sensintaffar, J.L. / Friberg, A. / Rossanese, O.W. / Lee, T. / Olejniczak, E.T. / Fesik, S.W.
History
DepositionDec 14, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2016Group: Database references / Structure summary
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Derived calculations / Category: pdbx_audit_support / pdbx_struct_oper_list
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 2023Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,1344
Polymers16,9601
Non-polymers1,1743
Water3,909217
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.327, 61.605, 42.216
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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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: 16960.330 Da / Num. of mol.: 1 / Fragment: unp residues 172-320
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-5WL / 6-chloranyl-~{N}-methylsulfonyl-3-(3-naphthalen-1-yloxypropyl)-1~{H}-indole-2-carboxamide


Mass: 456.942 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21ClN2O4S
#3: Chemical ChemComp-5WK / 2-[5-[1,1,2,2-tetrakis(fluoranyl)ethyl]-1~{H}-pyrazol-3-yl]phenol


Mass: 260.188 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H8F4N2O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 217 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.12 Å3/Da / Density % sol: 37.49 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / Details: PEG 3350, magnesium chloride, Bis-Tris

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.987 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jun 29, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 21659 / % possible obs: 98 % / Observed criterion σ(I): 2 / Redundancy: 7.5 % / Rmerge(I) obs: 0.05 / Rsym value: 0.04 / Net I/σ(I): 12.5
Reflection shellResolution: 1.5→1.56 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.36 / Mean I/σ(I) obs: 4.9 / % possible all: 97

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZBF

4zbf


Resolution: 1.5→21.108 Å / SU ML: 0.11 / Cross valid method: THROUGHOUT / σ(F): 1.39 / Phase error: 17.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1962 1103 5.09 %
Rwork0.1583 --
obs0.1602 21659 98.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.5→21.108 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1120 0 80 217 1417
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0191251
X-RAY DIFFRACTIONf_angle_d1.6241701
X-RAY DIFFRACTIONf_dihedral_angle_d19.746742
X-RAY DIFFRACTIONf_chiral_restr0.077177
X-RAY DIFFRACTIONf_plane_restr0.011212
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5003-1.56860.17151280.15022495X-RAY DIFFRACTION97
1.5686-1.65120.18631420.14552557X-RAY DIFFRACTION100
1.6512-1.75460.20981350.14212574X-RAY DIFFRACTION100
1.7546-1.890.18431500.14872568X-RAY DIFFRACTION100
1.89-2.08010.18821360.14862601X-RAY DIFFRACTION100
2.0801-2.38070.18641560.14542596X-RAY DIFFRACTION99
2.3807-2.99810.18721220.1672651X-RAY DIFFRACTION99
2.9981-21.11010.22051340.17592514X-RAY DIFFRACTION91
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.1348-0.2204-0.45910.95170.00230.82060.0596-0.14360.16630.04760.01530.0064-0.07870.0411-0.08680.0759-0.00860.00080.06020.00170.04911.331713.77219.5495
21.0875-0.26580.04680.88380.28890.98820.0053-0.0908-0.07240.08230.0292-0.00130.05090.008-0.02820.05340.0008-0.00610.04760.02160.057412.39445.80911.8357
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 171 through 235 )
2X-RAY DIFFRACTION2chain 'A' and (resid 236 through 320 )

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