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

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Basic information

Entry
Database: PDB / ID: 5fdo
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 / 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 / cellular homeostasis / cell fate determination / mitochondrial fusion / channel activity / 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 / release of cytochrome c from mitochondria / response to cytokine / Signaling by ALK fusions and activated point mutants / 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-5X2 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 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 16, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2016Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _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

Downloads & links

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


Theoretical massNumber of molelcules
Total (without water)70,5908
Polymers68,6024
Non-polymers1,9884
Water0
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,6482
Polymers17,1511
Non-polymers4971
Water0
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)17,6482
Polymers17,1511
Non-polymers4971
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,6482
Polymers17,1511
Non-polymers4971
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,6482
Polymers17,1511
Non-polymers4971
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)149.870, 149.870, 121.381
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number182
Space group name H-MP6322

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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: 17150.572 Da / Num. of mol.: 4 / 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-5X2 / 3-[3-(4-chloranyl-3,5-dimethyl-phenoxy)propyl]-~{N}-(phenylsulfonyl)-1~{H}-indole-2-carboxamide


Mass: 497.006 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H25ClN2O4S

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.01 Å3/Da / Density % sol: 59.19 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / Details: PEG 3350, BIS-TRIS, magnesium chloride / PH range: 6.0 - 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.987 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Apr 15, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 19447 / % possible obs: 95.6 % / Observed criterion σ(I): 1.5 / Redundancy: 4.7 % / Rmerge(I) obs: 0.1 / Rsym value: 0.09 / Net I/σ(I): 4.7
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 2.5 / % possible all: 80

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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: 4HW2

4hw2


Resolution: 2.8→29.776 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.5 / Phase error: 27.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2912 1020 5.25 %
Rwork0.2134 --
obs0.2174 19447 95.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.8→29.776 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4591 0 136 0 4727
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0124811
X-RAY DIFFRACTIONf_angle_d1.676479
X-RAY DIFFRACTIONf_dihedral_angle_d17.5082813
X-RAY DIFFRACTIONf_chiral_restr0.096700
X-RAY DIFFRACTIONf_plane_restr0.011816
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.94750.32991190.27552151X-RAY DIFFRACTION80
2.9475-3.1320.35341540.2782508X-RAY DIFFRACTION94
3.132-3.37350.33371410.24832653X-RAY DIFFRACTION98
3.3735-3.71250.30911560.21622682X-RAY DIFFRACTION99
3.7125-4.24830.27061600.19242704X-RAY DIFFRACTION99
4.2483-5.34740.24921590.18432777X-RAY DIFFRACTION100
5.3474-29.77780.27941310.20142952X-RAY DIFFRACTION99
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)
18.4637-0.2762-7.07572.55971.17646.2852-0.12380.8462-0.2733-0.5189-0.31090.2923-0.1862-1.04770.09790.22490.10560.09160.42680.08280.2655-8.409320.7037-14.8021
26.6724-1.6579-0.11816.3268-0.09132.82370.52580.9312-0.0138-0.9079-0.20610.046-0.9032-0.5101-0.2610.56640.1079-0.10210.37060.04490.2659-2.517528.3382-21.1478
33.9584-1.196-1.45474.825-0.07754.8026-0.0825-0.3985-0.20210.42610.1342-0.6126-0.24480.6071-0.09330.3264-0.0833-0.1980.2479-0.05430.60819.25816.2051-8.6345
43.0156-2.2156-1.59776.66782.4062.15960.1198-0.0747-0.00620.48250.217-0.4857-0.0940.1611-0.16870.1974-0.0395-0.024-0.0005-0.03830.29464.057123.9713-11.4753
52.7072-1.747-0.92465.96673.91533.4899-0.20320.1013-0.63620.34470.02520.2080.2623-0.25540.51360.2740.1936-0.03740.0758-0.26520.1826-1.611614.5664-11.237
62.8626-0.4413-0.47070.4702-0.27281.2840.1043-0.00050.3646-0.203-0.128-0.0042-0.3513-0.1817-0.10820.50270.20170.23510.1483-0.02410.3254-8.422631.1466-1.5144
78.22833.4941-0.82171.99680.51781.62210.05650.40380.98-0.35090.20230.3042-0.6553-0.2995-0.22860.77920.29840.15370.24720.09020.2994-8.001235.4481-12.7598
82.2293-0.1733-0.00092.479-0.77920.8907-0.03260.63210.4833-0.4706-0.03740.1321-0.12670.1185-0.06961.0093-0.2777-0.02550.25410.21320.15918.587550.8138-24.1409
95.27130.3903-0.41274.59521.68482.2423-0.25040.06020.00240.7351-0.22730.4660.0229-0.28870.37190.8129-0.16940.08680.2837-0.05510.522610.391443.8407-12.7565
104.91371.21042.42451.03421.78644.49080.1368-0.61380.40870.6001-0.10930.00220.44170.1308-0.03341.0758-0.34380.08240.5407-0.10330.348823.781346.753-4.5094
116.6832.1766-6.0956.7989-3.03576.87340.2277-1.26510.66862.1289-0.3718-0.5483-1.3458-0.03270.09040.697-0.0156-0.08310.3098-0.11570.695323.712831.0952-12.2471
122.98230.099-0.13852.87451.47072.6642-0.10010.30290.00090.0087-0.0060.1318-0.52980.1985-0.01510.6832-0.2689-0.060.28280.0260.141619.356643.7041-16.7994
130.3905-0.0639-0.15411.50120.15941.4512-0.04670.00810.1239-0.14670.1079-0.4825-0.5045-0.0375-0.04851.54720.4167-0.02950.3369-0.03240.4473-20.018258.9966-7.4111
144.36783.6039-0.15395.95664.46257.0674-0.19990.11741.1146-1.65790.52140.5351-2.3193-0.5413-0.49580.91340.02320.17470.3699-0.130.9303-13.420667.0071-12.9449
152.9217-1.07610.20332.0374-0.18080.92370.31820.5090.3982-0.3678-0.13060.3334-0.9246-0.20810.05961.28860.6629-0.18080.78820.06820.6713-29.083361.6165-17.6128
162.3529-1.3125-0.05852.6489-0.12670.865-0.14420.03320.5357-0.2786-0.1139-0.2146-0.4964-0.1263-0.14481.56990.5663-0.1760.3181-0.21750.4918-26.385456.0656-13.1408
171.7357-1.63860.48687.9631-3.30231.39470.05230.25580.1169-1.1893-0.14760.5785-1.0177-0.1530.07711.3393-0.1772-0.04470.40190.13050.69319.976462.101514.4115
181.58390.13490.49724.6137-3.16174.3525-0.6580.48760.7161-0.52060.49970.8352-1.5784-0.1021-0.00661.3356-0.3557-0.08730.69130.16580.969717.76372.442916.3735
192.43-0.176-0.71612.4766-0.88532.839-0.3330.36360.9174-0.85050.30460.407-0.80340.01470.03551.3436-0.4695-0.06420.59580.03440.601617.195666.730616.1919
202.7757-3.0497-0.35348.7136.04696.1204-0.4724-0.03560.1544-0.19260.41810.7585-0.0416-0.65420.09220.9837-0.22140.09110.8524-0.04590.69617.697664.18728.8365
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 171 through 190 )
2X-RAY DIFFRACTION2chain 'A' and (resid 191 through 223 )
3X-RAY DIFFRACTION3chain 'A' and (resid 224 through 254 )
4X-RAY DIFFRACTION4chain 'A' and (resid 255 through 280 )
5X-RAY DIFFRACTION5chain 'A' and (resid 281 through 301 )
6X-RAY DIFFRACTION6chain 'A' and (resid 302 through 309 )
7X-RAY DIFFRACTION7chain 'A' and (resid 310 through 320 )
8X-RAY DIFFRACTION8chain 'B' and (resid 171 through 205 )
9X-RAY DIFFRACTION9chain 'B' and (resid 206 through 239 )
10X-RAY DIFFRACTION10chain 'B' and (resid 240 through 254 )
11X-RAY DIFFRACTION11chain 'B' and (resid 255 through 260 )
12X-RAY DIFFRACTION12chain 'B' and (resid 261 through 320 )
13X-RAY DIFFRACTION13chain 'C' and (resid 171 through 189 )
14X-RAY DIFFRACTION14chain 'C' and (resid 190 through 203 )
15X-RAY DIFFRACTION15chain 'C' and (resid 204 through 254 )
16X-RAY DIFFRACTION16chain 'C' and (resid 255 through 320 )
17X-RAY DIFFRACTION17chain 'D' and (resid 171 through 190 )
18X-RAY DIFFRACTION18chain 'D' and (resid 191 through 260 )
19X-RAY DIFFRACTION19chain 'D' and (resid 261 through 310 )
20X-RAY DIFFRACTION20chain 'D' and (resid 311 through 320 )

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