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- PDB-5if4: Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) inhibitors us... -

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Basic information

Entry
Database: PDB / ID: 5if4
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 / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity / 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 / Signaling by ALK fusions and activated point mutants / 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 / cytoplasm / cytosol
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-6AK / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.392 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4984
Polymers36,0732
Non-polymers1,4252
Water2,054114
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,7492
Polymers18,0361
Non-polymers7131
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)18,7492
Polymers18,0361
Non-polymers7131
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.748, 87.842, 54.072
Angle α, β, γ (deg.)90.00, 99.68, 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.: 2 / 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-6AK / 4-{8-chloro-11-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl}-1-methyl-1H-indole-6-carboxylic acid


Mass: 712.664 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C39H39Cl2N5O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 114 / 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: 2.58 Å3/Da / Density % sol: 52.32 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 7.5 / 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: 0.9787 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 4, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 2.392→30 Å / Num. obs: 13659 / % possible obs: 94.1 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 2.8 % / Rmerge(I) obs: 0.058 / Rsym value: 0.105 / Net I/σ(I): 14.55
Reflection shellResolution: 2.4→2.48 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.215 / Mean I/σ(I) obs: 2.49 / % possible all: 98.5

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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: 2.392→29.305 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.45 / Phase error: 21.22
RfactorNum. reflection% reflection
Rfree0.2178 1365 10.01 %
Rwork0.156 --
obs0.1622 13642 93.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.392→29.305 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2425 0 100 114 2639
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082577
X-RAY DIFFRACTIONf_angle_d1.073489
X-RAY DIFFRACTIONf_dihedral_angle_d18.041495
X-RAY DIFFRACTIONf_chiral_restr0.056375
X-RAY DIFFRACTIONf_plane_restr0.009437
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3921-2.47760.29281260.20741139X-RAY DIFFRACTION87
2.4776-2.57670.29381300.19271162X-RAY DIFFRACTION89
2.5767-2.69390.25681320.18851188X-RAY DIFFRACTION92
2.6939-2.83580.27521340.18081205X-RAY DIFFRACTION92
2.8358-3.01330.24371350.17581216X-RAY DIFFRACTION94
3.0133-3.24570.23581360.16011228X-RAY DIFFRACTION95
3.2457-3.57180.22541420.15771277X-RAY DIFFRACTION97
3.5718-4.08750.18771410.13631267X-RAY DIFFRACTION98
4.0875-5.14530.17911420.12911284X-RAY DIFFRACTION97
5.1453-29.30760.18211470.1431311X-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)
10.43761.3702-0.70163.9983-1.7953.55040.0470.35470.3006-0.19020.1995-0.053-0.4984-0.1422-0.11890.3502-0.02460.010.28870.03080.26332.00085.27442.6541
22.8729-0.2881-0.97228.7201-0.60354.15140.0211-0.32130.1263-0.03510.0247-0.8206-0.11440.59330.04610.1752-0.0120.01390.3921-0.00320.1865.967-2.507513.8499
37.3623-1.8871-0.51774.47760.38477.1239-0.00730.7807-0.8724-1.1183-0.63290.63250.7629-0.03530.19920.60160.0482-0.00170.4065-0.0830.3542-2.8116-16.02271.8682
41.6366-0.86950.10384.19450.97052.1031-0.05320.0317-0.020.2826-0.00350.1530.5008-0.1149-0.01980.2035-0.0494-0.01410.18190.0420.179-1.3354-6.850811.8902
52.8811-1.6546-0.2366.31042.54644.39170.31140.6029-0.0799-0.3071-0.60060.6293-0.2409-1.17410.26780.16930.0036-0.04780.34560.0560.2462-7.3747-0.37957.7377
64.5923.01856.19065.3523.57599.03970.00010.05110.93420.2483-0.13050.0432-1.05140.20650.30670.4805-0.07980.0970.2618-0.04740.3694-0.441512.011717.6314
74.0735-0.37630.8253.0341-0.93192.66590.23070.3352-1.1092-0.465-0.08570.96670.5645-0.4337-0.16660.3198-0.0303-0.05510.3456-0.02280.456-19.8332-38.973911.0637
83.3071-0.34080.06112.3368-0.77854.6491-0.1233-0.3699-0.0970.72650.15550.6088-0.1465-0.4984-0.06780.2270.03860.00570.37830.05230.26-22.6257-27.813320.7397
98.6626-0.53884.52753.631-2.65369.384-0.43480.5681-0.04-0.3896-0.0267-0.2491-0.49220.40080.23460.3133-0.02490.01550.18650.02550.3039-13.3739-19.58438.3291
104.4708-3.25952.04794.2164-2.9325.1770.1860.1928-0.1187-0.1312-0.12650.10010.03490.12350.01330.1237-0.0358-0.00350.088-0.01130.2178-14.743-28.336114.5042
116.65580.36653.0690.24540.3331.5303-0.1087-0.3275-1.20970.08180.0910.4290.9639-0.77610.18270.315-0.07650.01840.3280.08450.4051-16.0943-41.785425.7553
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 172 through 202 )
2X-RAY DIFFRACTION2chain 'A' and (resid 203 through 235 )
3X-RAY DIFFRACTION3chain 'A' and (resid 236 through 246 )
4X-RAY DIFFRACTION4chain 'A' and (resid 247 through 283 )
5X-RAY DIFFRACTION5chain 'A' and (resid 284 through 308 )
6X-RAY DIFFRACTION6chain 'A' and (resid 309 through 322 )
7X-RAY DIFFRACTION7chain 'B' and (resid 171 through 202 )
8X-RAY DIFFRACTION8chain 'B' and (resid 203 through 235 )
9X-RAY DIFFRACTION9chain 'B' and (resid 236 through 254 )
10X-RAY DIFFRACTION10chain 'B' and (resid 255 through 308 )
11X-RAY DIFFRACTION11chain 'B' and (resid 309 through 324 )

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