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- PDB-8g3u: MBP-Mcl1 in complex with ligand 21 -

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Basic information

Entry
Database: PDB / ID: 8g3u
TitleMBP-Mcl1 in complex with ligand 21
ComponentsMaltodextrin-binding protein, Induced myeloid leukemia cell differentiation protein Mcl-1 chimera
KeywordsAPOPTOSIS / Myeloid cell leukemia 1 / Mcl-1 / B-cell lymphoma 2 / Bcl-2 / BH3 mimetic / Protein-protein interaction / Modulator / Cancer / Leukemia / Myeloma / Lymphoma / Physicochemical properties / ADME properties / Cardiotoxicity / Therapeutic window
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 / carbohydrate transmembrane transporter activity / negative regulation of anoikis / maltose binding ...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 / carbohydrate transmembrane transporter activity / negative regulation of anoikis / maltose binding / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / maltose transport / protein transmembrane transporter activity / maltodextrin transmembrane transport / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / 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 / 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 / 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 (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 / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain
Similarity search - Domain/homology
alpha-maltose / Chem-YKT / Maltodextrin-binding protein / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesSerratia sp. FS14 (bacteria)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsMiller, B.R. / Shaffer, P.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein-Protein Interaction Modulator with the Potential of Treating Hematological Malignancies.
Authors: Romanov-Michailidis, F. / Hsiao, C.C. / Urner, L.M. / Jerhaoui, S. / Surkyn, M. / Miller, B. / Vos, A. / Dominguez Blanco, M. / Bueters, R. / Vinken, P. / Bekkers, M. / Walker, D. / Pietrak, ...Authors: Romanov-Michailidis, F. / Hsiao, C.C. / Urner, L.M. / Jerhaoui, S. / Surkyn, M. / Miller, B. / Vos, A. / Dominguez Blanco, M. / Bueters, R. / Vinken, P. / Bekkers, M. / Walker, D. / Pietrak, B. / Eyckmans, W. / Dores-Sousa, J.L. / Joo Koo, S. / Lento, W. / Bauser, M. / Philippar, U. / Rombouts, F.J.R.
History
DepositionFeb 8, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 17, 2023Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: 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
Revision 1.2May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Maltodextrin-binding protein, Induced myeloid leukemia cell differentiation protein Mcl-1 chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,5795
Polymers57,3111
Non-polymers1,2684
Water5,747319
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: fluorescence resonance energy transfer, Enzymatic activity assessed by a HTRF binding assay utilizing the Bim BH3 peptide as the binding partner for terbium-labeled Mcl-1
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.324, 137.421, 38.563
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Maltodextrin-binding protein, Induced myeloid leukemia cell differentiation protein Mcl-1 chimera / 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
Source: (gene. exp.) Serratia sp. FS14 (bacteria), (gene. exp.) Homo sapiens (human)
Strain: FS14 / Gene: malE, JW3994, MCL1, BCL2L3 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A4P1LXE0, 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-YKT / (1'S,3aS,5R,16R,17S,19Z,21R,21aR)-6'-chloro-20-fluoro-21-{[(5S,9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]methyl}-21-methoxy-16,17-dimethyl-2,3,3',3a,4',16,17,18,21,21a-decahydro-2'H,6H,8H-15lambda~6~-spiro[10,12-(ethanediylidene)-15lambda~6~-furo[3,2-i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecine-7,1'-naphthalene]-13,15,15(4H,14H)-trione


Mass: 801.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H54ClFN4O7S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 319 / 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: 2.26 Å3/Da / Density % sol: 45.56 %
Crystal growTemperature: 285 K / Method: vapor diffusion / pH: 7.5 / Details: 0.11 M Mg Formate, 19.0% (w/v) PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jan 22, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.94→80.5 Å / Num. obs: 39870 / % possible obs: 99.9 % / Redundancy: 8 % / CC1/2: 0.996 / Rpim(I) all: 0.048 / Rrim(I) all: 0.135 / Rsym value: 0.126 / Net I/σ(I): 9.3
Reflection shellResolution: 1.943→1.977 Å / Redundancy: 8.4 % / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1955 / CC1/2: 0.552 / Rpim(I) all: 0.646 / Rrim(I) all: 1.868 / Rsym value: 1.749 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
autoPROC1.1.7data reduction
PHASERphasing
autoPROC1.1.7data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.94→80.5 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.931 / SU B: 9.295 / SU ML: 0.132 / Cross valid method: THROUGHOUT / ESU R: 0.184 / ESU R Free: 0.162 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23753 2044 5.1 %RANDOM
Rwork0.1954 ---
obs0.19754 37786 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 51.252 Å2
Baniso -1Baniso -2Baniso -3
1--1.16 Å2-0 Å2-0 Å2
2---1.94 Å20 Å2
3---3.09 Å2
Refinement stepCycle: LAST / Resolution: 1.94→80.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4043 0 86 319 4448
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0134262
X-RAY DIFFRACTIONr_bond_other_d0.0020.0174037
X-RAY DIFFRACTIONr_angle_refined_deg1.5211.6715800
X-RAY DIFFRACTIONr_angle_other_deg1.291.6069320
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1115531
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.31223.713202
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.0715.172725
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3551517
X-RAY DIFFRACTIONr_chiral_restr0.0740.2564
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024823
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02939
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.2543.642106
X-RAY DIFFRACTIONr_mcbond_other3.2543.6382105
X-RAY DIFFRACTIONr_mcangle_it3.9576.1252643
X-RAY DIFFRACTIONr_mcangle_other3.9566.1282644
X-RAY DIFFRACTIONr_scbond_it4.6664.2582156
X-RAY DIFFRACTIONr_scbond_other4.6654.2612157
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.0866.9483158
X-RAY DIFFRACTIONr_long_range_B_refined8.09635.0354878
X-RAY DIFFRACTIONr_long_range_B_other8.09134.5124821
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.943→1.994 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.374 151 -
Rwork0.312 2701 -
obs--98.75 %
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)
12.35350.36750.2631.8560.08211.8043-0.008-0.0266-0.02820.01880.07610.08960.075-0.2096-0.0680.2111-0.0256-0.00310.17540.00310.0084-3.22444.9513.104
22.0847-0.09960.30832.1941-0.6691.1682-0.05940.1193-0.0036-0.0997-0.0065-0.23470.06540.04550.0660.2296-0.00710.02130.14840.00110.033523.22250.7422.371
32.5870.72551.6544.4258-0.0213.5420.0635-0.1946-0.19220.1747-0.0220.42250.0087-0.3222-0.04150.20360.00020.04290.2195-0.00470.209116.09713.73412.989
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-200 - -86
2X-RAY DIFFRACTION1A65 - 116
3X-RAY DIFFRACTION2A-85 - 64
4X-RAY DIFFRACTION2A117 - 172
5X-RAY DIFFRACTION3A173 - 325

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