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

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Basic information

Entry
Database: PDB / ID: 5fdr
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 / 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-5X3 / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 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)74,5008
Polymers71,8614
Non-polymers2,6384
Water00
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6252
Polymers17,9651
Non-polymers6601
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)18,6252
Polymers17,9651
Non-polymers6601
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)18,6252
Polymers17,9651
Non-polymers6601
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)18,6252
Polymers17,9651
Non-polymers6601
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)35.040, 115.005, 95.327
Angle α, β, γ (deg.)90.00, 91.17, 90.00
Int Tables number4
Space group name H-MP1211

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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: 17965.369 Da / Num. of mol.: 4
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-5X3 / 5-[[6-chloranyl-3-[3-(4-chloranyl-3,5-dimethyl-phenoxy)propyl]-7-(3,5-dimethyl-1~{H}-pyrazol-4-yl)-1~{H}-indol-2-yl]carbonylsulfamoyl]furan-2-carboxylic acid


Mass: 659.537 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C30H28Cl2N4O7S

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.84 Å3/Da / Density % sol: 56.64 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / Details: PEG 3350, Bis-Tris, magnesium chloride

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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 scanner 300 mm plate / Detector: IMAGE PLATE / Date: Apr 7, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 22089 / % possible obs: 94.9 % / Observed criterion σ(I): 1.5 / Redundancy: 4.1 % / Rmerge(I) obs: 0.1 / Rsym value: 0.11 / Net I/σ(I): 5.3
Reflection shellResolution: 2.6→2.66 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 1.5 / % possible all: 87

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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: 2.6→28.751 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.49 / Phase error: 30.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2834 1079 4.88 %Random selection
Rwork0.2241 ---
obs0.2271 22089 94.92 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.6→28.751 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4761 0 176 0 4937
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.015027
X-RAY DIFFRACTIONf_angle_d1.3266791
X-RAY DIFFRACTIONf_dihedral_angle_d19.7423009
X-RAY DIFFRACTIONf_chiral_restr0.07729
X-RAY DIFFRACTIONf_plane_restr0.009857
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.71830.31411210.22722445X-RAY DIFFRACTION88
2.7183-2.86150.30271090.24132527X-RAY DIFFRACTION91
2.8615-3.04050.32691230.24322524X-RAY DIFFRACTION92
3.0405-3.2750.29871330.22992644X-RAY DIFFRACTION95
3.275-3.6040.29151440.22282669X-RAY DIFFRACTION98
3.604-4.12420.26761520.20612719X-RAY DIFFRACTION99
4.1242-5.19110.24911390.212735X-RAY DIFFRACTION98
5.1911-28.7530.28991580.23552747X-RAY DIFFRACTION98
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)
12.3953-0.3004-1.26343.9194-0.20632.33930.20790.4874-0.2058-0.3739-0.0814-0.1273-0.2234-0.2318-0.26080.2610.0268-0.15080.2361-0.05960.223935.50633.68745.0344
26.33970.1706-1.25040.18430.13592.511-0.2157-0.26780.6928-0.3370.1878-0.2402-0.45240.48020.20770.47740.0227-0.07010.1709-0.01740.251939.623311.309319.2484
33.1204-0.1836-1.28073.45790.99811.8448-0.0732-0.0602-0.1414-0.3340.2292-0.0724-0.05440.1064-0.10580.2156-0.0577-0.03560.18580.03250.140.0043.54088.473
41.5893-2.23890.93443.1631-0.96274.59110.49950.1297-0.75490.14810.0089-0.2921.16610.1327-0.26740.48580.0322-0.00510.1784-0.10080.483427.8842-32.20087.6419
50.1191-0.31880.11632.42261.05762.6130.070.201-0.112-0.0525-0.0514-0.41930.29190.6816-0.33490.3953-0.00930.02570.0489-0.2750.52934.6495-28.28161.7751
64.52150.8319-0.37494.5162-0.73096.7120.1485-0.5399-0.13210.3186-0.5603-0.3416-0.38080.07420.23540.17760.0106-0.00750.19080.03180.342629.7374-19.986622.1007
72.33110.3821.02793.65160.18154.6876-0.14640.03020.15590.1799-0.09120.45810.0065-0.31390.20090.28180.04970.01720.1419-0.07570.471726.8768-23.32859.0144
86.5438-0.11810.79935.7967-0.52825.97230.0477-1.2424-0.21790.75280.00230.4498-0.00530.195-0.03370.4153-0.02250.01730.23870.06720.200321.2399-11.285246.4263
93.90290.73961.70632.5481-0.12462.5689-0.0776-0.08370.4220.1917-0.22690.4846-0.0675-0.29120.28560.19690.0250.10110.2052-0.06080.3413.9075-4.976536.8288
102.6322-1.22090.7341.79040.38992.91660.09320.4298-0.2599-0.73950.6096-0.04440.25160.0774-0.28920.38410.0110.17710.2903-0.05730.211324.1281-13.26228.9909
117.56422.17410.85072.80631.24070.9911-0.0588-0.2114-0.5736-0.0197-0.35740.1376-0.1932-0.15790.18590.32060.02910.06790.2356-0.0668-0.12414.7335-9.824635.9616
127.32413.57412.6478.18642.08214.4591-0.277-0.2788-0.57090.48540.4548-0.68060.35810.3172-0.16620.24870.09890.06030.2224-0.00680.300326.8234-12.246638.5153
131.61-1.1421-0.64315.41041.25952.25740.0249-0.44840.07990.09740.6783-0.5902-0.1347-0.04480.10710.02920.2280.13630.4233-0.26650.046625.27734.38945.8402
141.18450.0456-1.43371.8422-0.43723.74580.4377-0.44651.46380.6207-0.1383-0.5164-1.1761-0.205-0.17150.51010.1596-0.15880.2256-0.30731.179646.194830.011642.1266
152.2364-1.4206-0.26592.82780.230.2567-0.3519-0.03010.81070.15670.1259-0.5704-0.120.29450.06430.29340.0062-0.01050.1508-0.04480.42753.172418.200139.4181
166.2603-0.8852-0.29414.7427-2.11457.2056-0.11831.02580.7048-0.7707-0.3872-0.23590.1925-0.50010.22520.2960.0381-0.05540.3767-0.02740.400342.905619.509625.3029
174.1132-0.9058-0.1773.2713-0.22846.0415-0.2483-0.36630.6889-0.07950.0343-0.0505-0.3596-0.47820.26270.24120.00590.00570.1754-0.13570.360444.032519.978339.4338
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 260 )
3X-RAY DIFFRACTION3chain 'A' and (resid 261 through 325 )
4X-RAY DIFFRACTION4chain 'B' and (resid 171 through 191 )
5X-RAY DIFFRACTION5chain 'B' and (resid 192 through 223 )
6X-RAY DIFFRACTION6chain 'B' and (resid 224 through 254 )
7X-RAY DIFFRACTION7chain 'B' and (resid 255 through 321 )
8X-RAY DIFFRACTION8chain 'C' and (resid 172 through 203 )
9X-RAY DIFFRACTION9chain 'C' and (resid 204 through 239 )
10X-RAY DIFFRACTION10chain 'C' and (resid 240 through 260 )
11X-RAY DIFFRACTION11chain 'C' and (resid 261 through 283 )
12X-RAY DIFFRACTION12chain 'C' and (resid 284 through 308 )
13X-RAY DIFFRACTION13chain 'C' and (resid 309 through 324 )
14X-RAY DIFFRACTION14chain 'D' and (resid 172 through 202 )
15X-RAY DIFFRACTION15chain 'D' and (resid 203 through 235 )
16X-RAY DIFFRACTION16chain 'D' and (resid 236 through 254 )
17X-RAY DIFFRACTION17chain 'D' and (resid 255 through 321 )

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