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- PDB-9pw6: Myeloid cell leukemia-1 (Mcl-1) complexed with compound 8 -

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Basic information

Entry
Database: PDB / ID: 9pw6
TitleMyeloid cell leukemia-1 (Mcl-1) complexed with compound 8
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / Mcl-1 / cancer / drug discovery
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 / response to cytokine ...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 / response to cytokine / extrinsic apoptotic signaling pathway in absence of ligand / 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 / cytoplasm / cytosol
Similarity search - Function
Apoptosis regulator, Mcl-1 / 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 ...Apoptosis regulator, Mcl-1 / 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
Similarity search - Domain/homology
: / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.068 Å
AuthorsZhao, B. / Fesik, S.W.
Funding support Germany, 1items
OrganizationGrant numberCountry
Boehringer Ingelheim Fonds (BIF) Germany
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model.
Authors: Tarr, J.C. / Jeon, K. / Veerasamy, N. / Aichinger, M. / Salovich, J.M. / Zhao, B. / Sensintaffar, J.L. / Arnhof, H. / Wunberg, T. / Sgubin, D. / Arnold, A. / Vekariya, R.H. / Christov, P.P. ...Authors: Tarr, J.C. / Jeon, K. / Veerasamy, N. / Aichinger, M. / Salovich, J.M. / Zhao, B. / Sensintaffar, J.L. / Arnhof, H. / Wunberg, T. / Sgubin, D. / Arnold, A. / Vekariya, R.H. / Christov, P.P. / Kim, K. / Fuchs, J.E. / Karier, P. / Betzemeier, B. / Van Meveren, M. / Miriyala, N. / Olejniczak, E.T. / Engelhardt, H. / Lee, T. / McConnell, D. / Fesik, S.W.
History
DepositionAug 4, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 17, 2025Provider: repository / Type: Initial release

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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)36,4434
Polymers34,9022
Non-polymers1,5412
Water2,666148
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2222
Polymers17,4511
Non-polymers7711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2222
Polymers17,4511
Non-polymers7711
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.613, 87.678, 50.348
Angle α, β, γ (deg.)90.000, 102.422, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21A

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: ASP / Beg label comp-ID: ASP / End auth comp-ID: PHE / End label comp-ID: PHE / Auth asym-ID: A / Label asym-ID: A / Auth seq-ID: 172 - 319 / Label seq-ID: 3 - 150

Dom-ID
1
2

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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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: 17450.881 Da / Num. of mol.: 2
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-A1CL3 / 7-[(4R,5S,6P)-7-chloro-10-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-4-methyl-1-oxo-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl]-1-(2-methoxyethyl)-5-methyl-1H-indole-2-carboxylic acid


Mass: 770.743 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C42H45Cl2N5O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 148 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.31 Å3/Da / Density % sol: 46.72 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 25-30% PEG 3350, 0.1 M Bis-TRIS pH 6.5, 0.2 M MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9785 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 10, 2016
RadiationMonochromator: C(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
ReflectionResolution: 2.06→28.386 Å / Num. obs: 18204 / % possible obs: 97.79 % / Redundancy: 2.2 % / CC1/2: 0.983 / CC star: 0.996 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.06 / Χ2: 1.526 / Net I/σ(I): 12.2
Reflection shellResolution: 2.06→2.1 Å / Redundancy: 1.6 % / Rmerge(I) obs: 0.357 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 774 / CC1/2: 0.214 / CC star: 0.593 / Rpim(I) all: 0.327 / Χ2: 0.885 / % possible all: 94

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
XDSdata scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.068→28.386 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.794 / SU B: 6.045 / SU ML: 0.157 / Cross valid method: FREE R-VALUE / ESU R: 0.274 / ESU R Free: 0.226
Details: Hydrogens have been used if present in the input file
RfactorNum. reflection% reflection
Rfree0.2582 839 4.75 %
Rwork0.1894 16824 -
all0.193 --
obs-17663 87.976 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 31.793 Å2
Baniso -1Baniso -2Baniso -3
1-0.414 Å20 Å20.586 Å2
2---1.409 Å2-0 Å2
3---0.672 Å2
Refinement stepCycle: LAST / Resolution: 2.068→28.386 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2417 0 108 148 2673
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0122577
X-RAY DIFFRACTIONr_angle_refined_deg1.8321.93486
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6715299
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.333527
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.45710460
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.36310120
X-RAY DIFFRACTIONr_chiral_restr0.120.2370
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.021950
X-RAY DIFFRACTIONr_nbd_refined0.2250.21311
X-RAY DIFFRACTIONr_nbtor_refined0.3010.21816
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2170.2173
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2660.257
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1770.215
X-RAY DIFFRACTIONr_mcbond_it3.772.9651202
X-RAY DIFFRACTIONr_mcangle_it5.5675.3151499
X-RAY DIFFRACTIONr_scbond_it4.4973.2571375
X-RAY DIFFRACTIONr_scangle_it6.4395.7821987
X-RAY DIFFRACTIONr_lrange_it10.48138.54211570
X-RAY DIFFRACTIONr_ncsr_local_group_10.150.054576
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.149710.05007
12AX-RAY DIFFRACTIONLocal ncs0.149710.05007
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.068-2.1210.353520.2851065X-RAY DIFFRACTION74.866
2.121-2.180.257550.2511096X-RAY DIFFRACTION80.4895
2.18-2.2430.288510.2141120X-RAY DIFFRACTION83.2859
2.243-2.3110.279530.2081087X-RAY DIFFRACTION84.3819
2.311-2.3870.312620.21102X-RAY DIFFRACTION87.453
2.387-2.4710.331520.1941037X-RAY DIFFRACTION86.4972
2.471-2.5640.285470.2161053X-RAY DIFFRACTION88.4244
2.564-2.6680.221530.187999X-RAY DIFFRACTION89.3798
2.668-2.7860.235600.182976X-RAY DIFFRACTION91.117
2.786-2.9220.275480.184940X-RAY DIFFRACTION91.3124
2.922-3.0790.233520.182892X-RAY DIFFRACTION91.2959
3.079-3.2650.325380.177862X-RAY DIFFRACTION92.1187
3.265-3.490.189420.168835X-RAY DIFFRACTION93.3972
3.49-3.7680.202440.163762X-RAY DIFFRACTION94.49
3.768-4.1250.185290.152710X-RAY DIFFRACTION93.073
4.125-4.6080.231340.137634X-RAY DIFFRACTION92.1379
4.608-5.3130.166210.168562X-RAY DIFFRACTION92.8344
5.313-6.4880.266230.205500X-RAY DIFFRACTION95.438
6.488-9.0960.165120.215378X-RAY DIFFRACTION92.6366
9.096-28.3860.524110.271214X-RAY DIFFRACTION90.3614

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