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

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Basic information

Entry
Database: PDB / ID: 9bcg
TitleMyeloid cell leukemia-1 (Mcl-1) complexed with compound
ComponentsMaltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / Mcl-1 / drug discovery
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / Bcl-2 family protein complex / mitochondrial fusion / BH domain binding / detection of maltose stimulus / maltose transport complex / BH3 domain binding / carbohydrate transport ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / Bcl-2 family protein complex / mitochondrial fusion / BH domain binding / detection of maltose stimulus / maltose transport complex / BH3 domain binding / carbohydrate transport / maltose binding / protein transmembrane transporter activity / maltose transport / negative regulation of anoikis / maltodextrin transmembrane transport / carbohydrate transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of autophagy / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / release of cytochrome c from mitochondria / response to cytokine / channel activity / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / outer membrane-bounded periplasmic space / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / mitochondrial outer membrane / periplasmic space / positive regulation of apoptotic process / protein heterodimerization activity / DNA damage response / negative regulation of apoptotic process / mitochondrion / nucleoplasm / membrane / nucleus / cytosol / cytoplasm
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 (B-Cell lymphoma); contains BH1, BH2 regions / Bcl-2 family / Bcl-2, Bcl-2 homology region 1-3 ...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 (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 / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein
Similarity search - Domain/homology
alpha-maltose / : / Maltose/maltodextrin-binding periplasmic protein / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.898 Å
AuthorsZhao, B. / Fesik, S.W.
Funding support Germany, 1items
OrganizationGrant numberCountry
Boehringer Ingelheim Fonds (BIF) Germany
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors.
Authors: Tarr, J.C. / Salovich, J.M. / Aichinger, M. / Jeon, K. / Veerasamy, N. / Sensintaffar, J.L. / Arnhof, H. / Samwer, M. / Christov, P.P. / Kim, K. / Wunberg, T. / Schweifer, N. / Trapani, F. / ...Authors: Tarr, J.C. / Salovich, J.M. / Aichinger, M. / Jeon, K. / Veerasamy, N. / Sensintaffar, J.L. / Arnhof, H. / Samwer, M. / Christov, P.P. / Kim, K. / Wunberg, T. / Schweifer, N. / Trapani, F. / Arnold, A. / Martin, F. / Zhao, B. / Miriyala, N. / Sgubin, D. / Fogarty, S. / Moore, W.J. / Stott, G.M. / Olejniczak, E.T. / Engelhardt, H. / Rudolph, D. / Lee, T. / McConnell, D.B. / Fesik, S.W.
History
DepositionApr 9, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2024Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 4, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Sep 11, 2024Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,2843
Polymers57,1691
Non-polymers1,1152
Water10,647591
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.453, 136.858, 38.624
Angle α, β, γ (deg.)90, 90, 90
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-952-

HOH

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Components

#1: Protein Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1 / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Bcl-2-like protein 3 / Bcl2-L- ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Bcl-2-like protein 3 / Bcl2-L-3 / Bcl-2-related protein EAT/mcl1 / mcl1/EAT


Mass: 57168.727 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: malE, b4034, JW3994, MCL1, BCL2L3 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P0AEX9, UniProt: Q07820
#2: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose


Type: oligosaccharide, Oligosaccharide / Class: Nutrient / Mass: 342.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: oligosaccharide / References: alpha-maltose
DescriptorTypeProgram
DGlcpa1-4DGlcpa1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1a_1-5]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][a-D-Glcp]{[(4+1)][a-D-Glcp]{}}LINUCSPDB-CARE
#3: Chemical ChemComp-A1ALT / 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]-4,5-dimethoxy-1-methyl-1H-indole-2-carboxylic acid


Mass: 772.716 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H43Cl2N5O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 591 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.3 Å3/Da / Density % sol: 46.5 %
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 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.978 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Apr 4, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 1.898→38.654 Å / Num. obs: 41247 / % possible obs: 96.4 % / Redundancy: 5.8 % / Rmerge(I) obs: 0.142 / Rpim(I) all: 0.061 / Rrim(I) all: 0.156 / Net I/σ(I): 10.4
Reflection shellResolution: 1.9→1.93 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.613 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1991 / CC1/2: 0.165 / CC star: 0.532 / Rpim(I) all: 0.326 / Rrim(I) all: 0.699 / % possible all: 96.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.898→38.654 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.94 / SU B: 4.534 / SU ML: 0.121 / Cross valid method: FREE R-VALUE / ESU R: 0.165 / ESU R Free: 0.142
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2103 2058 4.992 %
Rwork0.1755 39167 -
all0.177 --
obs-41225 96.496 %
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: 23.961 Å2
Baniso -1Baniso -2Baniso -3
1-0.135 Å20 Å2-0 Å2
2---0.573 Å20 Å2
3---0.438 Å2
Refinement stepCycle: LAST / Resolution: 1.898→38.654 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4003 0 77 591 4671
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0124210
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163921
X-RAY DIFFRACTIONr_angle_refined_deg1.4751.8195736
X-RAY DIFFRACTIONr_angle_other_deg0.5211.7599055
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8775525
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.58210.19226
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.32110690
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.01410186
X-RAY DIFFRACTIONr_chiral_restr0.0710.2628
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024974
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02929
X-RAY DIFFRACTIONr_nbd_refined0.220.2926
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1890.23628
X-RAY DIFFRACTIONr_nbtor_refined0.1840.22153
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0770.22096
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2160.2443
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1380.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1720.219
X-RAY DIFFRACTIONr_nbd_other0.2360.246
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2540.227
X-RAY DIFFRACTIONr_mcbond_it1.9482.1532079
X-RAY DIFFRACTIONr_mcbond_other1.9482.1532079
X-RAY DIFFRACTIONr_mcangle_it3.0823.8612602
X-RAY DIFFRACTIONr_mcangle_other3.0823.8622603
X-RAY DIFFRACTIONr_scbond_it2.742.4542131
X-RAY DIFFRACTIONr_scbond_other2.742.4552132
X-RAY DIFFRACTIONr_scangle_it4.4664.3493131
X-RAY DIFFRACTIONr_scangle_other4.4654.3493132
X-RAY DIFFRACTIONr_lrange_it6.81227.37319122
X-RAY DIFFRACTIONr_lrange_other6.51626.58218464
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.898-1.9470.3031380.32526960.32431160.9250.91490.94990.297
1.947-20.2771340.28626860.28629920.9370.93594.25130.254
2-2.0580.3071460.25826730.26129540.9280.94795.42990.223
2.058-2.1210.2921230.24426020.24628650.9340.95495.11340.207
2.121-2.1910.2931370.22825260.23127690.9340.9696.17190.188
2.191-2.2670.2381350.19824700.227100.9590.9796.12550.162
2.267-2.3530.2751190.19123750.19525750.9510.97396.85440.152
2.353-2.4480.2391290.17823210.18125290.9620.97896.87620.144
2.448-2.5570.2151260.16822020.17124000.9690.982970.137
2.557-2.6810.2011060.15621390.15823040.9720.98497.43920.13
2.681-2.8250.2311020.16420330.16721900.9620.98297.48860.138
2.825-2.9960.2241080.1619510.16321020.9680.98397.95430.136
2.996-3.2010.182890.15618420.15719770.980.98597.67320.136
3.201-3.4560.177920.15417140.15618340.9790.98598.47330.138
3.456-3.7830.1971030.14215730.14516970.9750.98898.76250.134
3.783-4.2240.137720.12314720.12415650.990.9998.65810.12
4.224-4.8680.121670.11513150.11513970.990.99298.92630.115
4.868-5.9380.161650.13311020.13411800.9840.9998.89830.132
5.938-8.3010.19390.1559120.1579570.9780.98699.3730.156
8.301-38.6540.146280.1525630.1525980.990.98298.82940.162

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