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- PDB-5iez: Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) inhibitors us... -

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Basic information

Entry
Database: PDB / ID: 5iez
TitleDiscovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) inhibitors using Structure-Based Design
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
Keywordsapoptosis/apoptosis inhibitor / Myeloid Cell Leukemia-1 / Bcl-2 / apoptosis / 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-6AL / 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: FEBS Lett. / Year: 2017
Title: Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.
Authors: Lee, T. / Bian, Z. / Zhao, B. / Hogdal, L.J. / Sensintaffar, J.L. / Goodwin, C.M. / Belmar, J. / Shaw, S. / Tarr, J.C. / Veerasamy, N. / Matulis, S.M. / Koss, B. / Fischer, M.A. / Arnold, A. ...Authors: Lee, T. / Bian, Z. / Zhao, B. / Hogdal, L.J. / Sensintaffar, J.L. / Goodwin, C.M. / Belmar, J. / Shaw, S. / Tarr, J.C. / Veerasamy, N. / Matulis, S.M. / Koss, B. / Fischer, M.A. / Arnold, A.L. / Camper, D.V. / Browning, C.F. / Rossanese, O.W. / Budhraja, A. / Opferman, J. / Boise, L.H. / Savona, M.R. / Letai, A. / Olejniczak, E.T. / Fesik, S.W.
History
DepositionFeb 25, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 18, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2017Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 6, 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

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)74,6248
Polymers72,1464
Non-polymers2,4784
Water1,69394
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6562
Polymers18,0361
Non-polymers6201
Water181
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)18,6562
Polymers18,0361
Non-polymers6201
Water181
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)18,6562
Polymers18,0361
Non-polymers6201
Water181
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)18,6562
Polymers18,0361
Non-polymers6201
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.914, 136.046, 63.499
Angle α, β, γ (deg.)90.00, 101.62, 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: 18036.445 Da / Num. of mol.: 4 / Fragment: unp residues 172-327
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-6AL / 3-({6-chloro-3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-indole-2-carbonyl}amino)benzoic acid


Mass: 619.538 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H32Cl2N4O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 94 / 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: 2.34 Å3/Da / Density % sol: 47.45 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 6.6 / 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-F / Wavelength: 0.9787 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: May 1, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 2.6→30 Å / Num. obs: 18621 / % possible obs: 90.8 % / Observed criterion σ(F): 2 / Redundancy: 2.5 % / Rmerge(I) obs: 0.047 / Rsym value: 0.109 / Net I/σ(I): 24.23
Reflection shellResolution: 2.6→2.76 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.312 / Mean I/σ(I) obs: 2.93 / % possible all: 82.6

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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 / Resolution: 2.6→29.841 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.5 / Phase error: 29.68
RfactorNum. reflection% reflection
Rfree0.2769 905 4.88 %
Rwork0.1943 --
obs0.1982 18533 90.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.6→29.841 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4756 0 172 94 5022
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095027
X-RAY DIFFRACTIONf_angle_d1.2136801
X-RAY DIFFRACTIONf_dihedral_angle_d17.6432923
X-RAY DIFFRACTIONf_chiral_restr0.064736
X-RAY DIFFRACTIONf_plane_restr0.008864
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.76280.36771410.23982653X-RAY DIFFRACTION82
2.7628-2.9760.32221470.23792766X-RAY DIFFRACTION86
2.976-3.27510.31371770.23022907X-RAY DIFFRACTION91
3.2751-3.74820.32821440.19313042X-RAY DIFFRACTION94
3.7482-4.71940.21951320.1653125X-RAY DIFFRACTION96
4.7194-29.84330.22721640.17413135X-RAY DIFFRACTION96
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)
12.6413.6633-0.96255.3244-0.33754.0528-0.2987-0.16040.71540.04530.2285-0.3272-0.44570.08350.03310.2926-0.0138-0.02520.1646-0.01140.37210.16425.412434.3543
23.3912-1.465-0.22641.3888-1.25342.3357-0.08560.71590.3445-0.4077-0.0891-0.88320.4463-0.38480.08380.72770.01650.12990.2906-0.13650.45993.989711.352536.5506
32.41572.4734-0.36724.85771.15095.04120.04170.64720.65260.3610.06141.1126-0.8338-1.0390.20490.23930.0667-0.0130.2982-0.00950.39452.07663.237525.528
47.23212.33921.35126.246-1.1352.02230.1480.3409-1.14230.1054-0.6524-0.07690.4805-0.29170.21590.5452-0.00060.13770.344-0.07440.34583.6947-16.466930.9536
52.57530.24490.04815.8185-2.73023.3035-0.4575-0.3837-0.21020.34720.2282-0.08610.63460.2590.02850.54230.17880.09560.33560.02980.361514.4436-12.331538.0692
62.30160.7751-0.24513.0791-1.57223.8648-0.1837-0.24830.0009-0.48390.015-0.32640.45070.20260.0610.2706-0.00780.01420.2171-0.06130.26988.0301-6.720830.8275
74.14463.0647-3.8045.166-3.71983.9310.4539-0.21840.05590.145-0.3909-0.5204-0.87360.1973-0.14260.36250.0432-0.02940.2272-0.0490.347316.4451-0.108632.2569
89.26040.20848.86132.6239-0.76479.5869-0.65990.85291.89380.029-0.9278-0.0178-1.78370.3616-0.04390.54050.2790.18680.0943-0.0870.394510.36337.397419.075
93.22111.0744-1.1644.22780.35063.8894-0.2818-0.1409-0.4394-0.30440.26390.74310.6352-0.10450.03490.4378-0.0305-0.01210.22120.08320.2744-1.75-0.39659.6479
104.31960.2714-0.42172.65881.07774.0786-0.20620.19420.2433-0.57030.3312-0.3688-0.1794-0.3306-0.10690.4263-0.02970.02650.22730.00640.33673.477319.076556.7339
112.2238-0.12520.77522.8037-2.31194.608-0.0534-0.1268-0.09630.2101-0.2102-0.0693-0.08790.2320.28080.24320.01160.04550.1696-0.03770.25854.49595.583462.6223
125.8002-0.8999-0.47651.30250.46851.3744-0.32180.9522-0.03740.12110.0245-0.1338-0.20240.1331-0.02930.6285-0.05180.14030.2548-0.03490.403922.637842.342948.523
133.0374-1.1014-1.27632.55390.54090.9725-0.0874-0.3526-0.13590.03150.1722-0.2757-0.00640.2421-0.0260.5514-0.04280.02390.25270.00520.338521.295131.169758.0614
143.5665-3.0139-0.81116.27412.59692.1222-0.006-0.08280.2288-0.1505-0.1849-0.0178-0.1604-0.22660.18230.4218-0.03170.13870.18940.02750.351816.663336.464856.0277
153.3269-1.6421-4.45695.4061-1.20978.47990.9577-0.45420.08390.06330.815-0.1857-1.62451.5994-1.26110.97940.14080.15340.5733-0.14530.531424.513553.477564.8156
166.2907-0.21950.47655.5678-1.65756.0874-0.40520.6992-0.3411-2.23550.02330.42360.8164-0.28180.09410.6733-0.1008-0.15480.31220.00620.58730.088832.669517.6003
175.6456-0.7979-2.46874.5154-0.08057.59030.3062-0.2876-1.05360.6526-0.4220.67410.58380.1735-0.03180.4316-0.04-0.1690.39350.11210.5424-4.572129.571527.9843
185.246-0.2841.90084.3648-2.30442.8801-0.3119-0.08140.7392-0.56130.1157-0.3201-0.1812-0.25260.13390.2893-0.06880.05710.2092-0.05360.48681.88549.443726.8257
192.5558-1.50450.80016.3161-3.36522.69860.23690.1687-0.277-0.5254-0.3967-0.30140.21810.2490.13180.5447-0.03260.06030.232-0.0230.31773.637535.665525.1883
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 171:190 )A171 - 190
2X-RAY DIFFRACTION2( CHAIN A AND RESID 191:202 )A191 - 202
3X-RAY DIFFRACTION3( CHAIN A AND RESID 203:223 )A203 - 223
4X-RAY DIFFRACTION4( CHAIN A AND RESID 224:235 )A224 - 235
5X-RAY DIFFRACTION5( CHAIN A AND RESID 236:254 )A236 - 254
6X-RAY DIFFRACTION6( CHAIN A AND RESID 255:283 )A255 - 283
7X-RAY DIFFRACTION7( CHAIN A AND RESID 284:308 )A284 - 308
8X-RAY DIFFRACTION8( CHAIN A AND RESID 309:321 )A309 - 321
9X-RAY DIFFRACTION9( CHAIN B AND RESID 172:223 )B172 - 223
10X-RAY DIFFRACTION10( CHAIN B AND RESID 224:254 )B224 - 254
11X-RAY DIFFRACTION11( CHAIN B AND RESID 255:323 )B255 - 323
12X-RAY DIFFRACTION12( CHAIN C AND RESID 172:202 )C172 - 202
13X-RAY DIFFRACTION13( CHAIN C AND RESID 203:254 )C203 - 254
14X-RAY DIFFRACTION14( CHAIN C AND RESID 255:318 )C255 - 318
15X-RAY DIFFRACTION15( CHAIN C AND RESID 319:323 )C319 - 323
16X-RAY DIFFRACTION16( CHAIN D AND RESID 171:203 )D171 - 203
17X-RAY DIFFRACTION17( CHAIN D AND RESID 204:223 )D204 - 223
18X-RAY DIFFRACTION18( CHAIN D AND RESID 224:254 )D224 - 254
19X-RAY DIFFRACTION19( CHAIN D AND RESID 255:323 )D255 - 323

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