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- PDB-8qso: Crystal structure of human Mcl-1 in complex with compound 1 -

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Basic information

Entry
Database: PDB / ID: 8qso
TitleCrystal structure of human Mcl-1 in complex with compound 1
ComponentsMaltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsTRANSFERASE / Mcl-1 / Inhibitor
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 / detection of maltose stimulus / maltose transport complex / BH3 domain binding / maltose binding ...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 / detection of maltose stimulus / maltose transport complex / BH3 domain binding / maltose binding / maltose transport / maltodextrin transmembrane transport / carbohydrate transport / carbohydrate transmembrane transporter activity / negative regulation of anoikis / protein 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 / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / 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 / outer membrane-bounded periplasmic space / regulation of apoptotic process / Interleukin-4 and Interleukin-13 signaling / mitochondrial outer membrane / periplasmic space / 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 / 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
: / 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: 2.106 Å
AuthorsHekking, K.F.W. / Gremmen, S. / Maroto, S. / Keefe, A.D. / Zhang, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.
Authors: Hekking, K.F.W. / Maroto, S. / van Kekem, K. / Haasjes, F.S. / Slootweg, J.C. / Oude Alink, P.G.B. / Dirks, R. / Sardana, M. / Bolster, M.G. / Kuijpers, B. / Smith, D. / Doodeman, R. / ...Authors: Hekking, K.F.W. / Maroto, S. / van Kekem, K. / Haasjes, F.S. / Slootweg, J.C. / Oude Alink, P.G.B. / Dirks, R. / Sardana, M. / Bolster, M.G. / Kuijpers, B. / Smith, D. / Doodeman, R. / Scheepstra, M. / Zech, B. / Mulvihill, M. / Renzetti, L.M. / Babiss, L. / Centrella, P.A. / Clark, M.A. / Cuozzo, J.W. / Guie, M.A. / Sigel, E. / Habeshian, S. / Hupp, C.D. / Liu, J. / Thomson, H.A. / Zhang, Y. / Keefe, A.D. / Muller, G. / Gremmen, S.
History
DepositionOct 10, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 14, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _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)58,4563
Polymers57,3111
Non-polymers1,1452
Water5,981332
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area850 Å2
ΔGint8 kcal/mol
Surface area21440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.528, 90.804, 94.104
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 57310.883 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: MBP-MCL1 fusion protein as in PDB entry 4WGI. The construct contains (N-terminus to C-terminus): (1) a Gly residue; (2) residues K27-T392 of E. coli malE (P0AEY0); (3) a Gly-Ser linker; (4) ...Details: MBP-MCL1 fusion protein as in PDB entry 4WGI. The construct contains (N-terminus to C-terminus): (1) a Gly residue; (2) residues K27-T392 of E. coli malE (P0AEY0); (3) a Gly-Ser linker; (4) residues E173-V321 of H. sapiens MCL1 (Q07820) and the mutations K194A, K197A and R201A,MBP-MCL1 fusion protein as in PDB entry 4WGI. The construct contains (N-terminus to C-terminus): (1) a Gly residue; (2) residues K27-T392 of E. coli malE (P0AEY0); (3) a Gly-Ser linker; (4) residues E173-V321 of H. sapiens MCL1 (Q07820) and the mutations K194A, K197A and R201A
Source: (gene. exp.) Homo sapiens (human) / Gene: malE, b4034, JW3994, MCL1, BCL2L3 / Production host: Escherichia coli (E. coli) / References: UniProt: P0AEX9, UniProt: Q07820
#2: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose


Type: oligosaccharide / Mass: 342.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
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-WXW / (13S,16R,19S)-16-benzyl-43-ethoxy-N-methyl-7,11,14,17-tetraoxo-13-phenyl-5-oxa-2,8,12,15,18-pentaaza-1(1,4),4(1,2)-dibenzena-9(1,4)-cyclohexanacycloicosaphane-19-carboxamide / 4-O-BETA-METHYL-D-GLUCOPYRANOSYL CELLOBIONOLACTAM OXIME


Mass: 802.957 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C46H54N6O7 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 332 / 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: 2.85 Å3/Da / Density % sol: 56.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 1.94 M Ammonium Citrate pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jun 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 2.106→28.217 Å / Num. obs: 37579 / % possible obs: 97.3 % / Redundancy: 3 % / CC1/2: 0.993 / Rmerge(I) obs: 0.098 / Rpim(I) all: 0.06 / Rrim(I) all: 0.116 / Net I/σ(I): 5.1
Reflection shellResolution: 2.106→2.182 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.824 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 3776 / CC1/2: 0.577 / Rpim(I) all: 0.521 / Rrim(I) all: 0.984 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0415refinement
autoPROC1.1.7 20230222data processing
XDSJan 10, 2022data reduction
Aimless0.7.9data scaling
STARANISO2.3.92data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.106→28.217 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.94 / SU B: 9.003 / SU ML: 0.21 / Cross valid method: FREE R-VALUE / ESU R: 0.229 / ESU R Free: 0.193
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2496 1888 5.088 %
Rwork0.208 35222 -
all0.21 --
obs-37110 96.04 %
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: 46.24 Å2
Baniso -1Baniso -2Baniso -3
1--3.06 Å2-0 Å20 Å2
2--3.586 Å2-0 Å2
3----0.525 Å2
Refinement stepCycle: LAST / Resolution: 2.106→28.217 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4043 0 82 332 4457
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0124233
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164024
X-RAY DIFFRACTIONr_angle_refined_deg0.8971.6735738
X-RAY DIFFRACTIONr_angle_other_deg0.3141.69289
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8115519
X-RAY DIFFRACTIONr_dihedral_angle_2_deg4.614519
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.91110713
X-RAY DIFFRACTIONr_dihedral_angle_6_deg13.34210186
X-RAY DIFFRACTIONr_chiral_restr0.0450.2628
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.024966
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02958
X-RAY DIFFRACTIONr_nbd_refined0.1960.21002
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1790.23753
X-RAY DIFFRACTIONr_nbtor_refined0.1760.22130
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0730.22060
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1480.2250
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0220.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1390.215
X-RAY DIFFRACTIONr_nbd_other0.1350.276
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2090.217
X-RAY DIFFRACTIONr_mcbond_it2.0174.8222078
X-RAY DIFFRACTIONr_mcbond_other2.0114.8222076
X-RAY DIFFRACTIONr_mcangle_it3.3328.6682596
X-RAY DIFFRACTIONr_mcangle_other3.3278.6692596
X-RAY DIFFRACTIONr_scbond_it2.3425.0862155
X-RAY DIFFRACTIONr_scbond_other2.3415.0862156
X-RAY DIFFRACTIONr_scangle_it4.0689.2043142
X-RAY DIFFRACTIONr_scangle_other4.0689.2033143
X-RAY DIFFRACTIONr_lrange_it6.54549.8165031
X-RAY DIFFRACTIONr_lrange_other6.50747.9674984
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.106-2.1610.3711300.3562388X-RAY DIFFRACTION89.3859
2.161-2.220.3441610.3362421X-RAY DIFFRACTION94.7871
2.22-2.2830.351190.3742453X-RAY DIFFRACTION96.7645
2.283-2.3530.3271270.3112400X-RAY DIFFRACTION98.9428
2.353-2.430.3491380.2932353X-RAY DIFFRACTION99.0851
2.43-2.5140.281220.2652283X-RAY DIFFRACTION98.8085
2.514-2.6090.3361070.2482177X-RAY DIFFRACTION97.1501
2.609-2.7140.281110.2442071X-RAY DIFFRACTION96.4207
2.714-2.8340.2891110.2441972X-RAY DIFFRACTION95.2011
2.834-2.970.313850.2331922X-RAY DIFFRACTION96.1207
2.97-3.1290.304980.2321851X-RAY DIFFRACTION98.2854
3.129-3.3170.2691000.2091751X-RAY DIFFRACTION98.4575
3.317-3.5420.264860.1931650X-RAY DIFFRACTION97.4186
3.542-3.8210.183810.1731530X-RAY DIFFRACTION96.9314
3.821-4.1780.201700.1671414X-RAY DIFFRACTION96.4889
4.178-4.6580.165680.1411276X-RAY DIFFRACTION95.3868
4.658-5.3550.195560.1411093X-RAY DIFFRACTION91.9936
5.355-6.50.253470.184969X-RAY DIFFRACTION93.5543
6.5-8.9580.214420.158770X-RAY DIFFRACTION93.7644
8.958-28.2170.175290.16478X-RAY DIFFRACTION90.5357

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