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- PDB-8g3x: MBP-Mcl1 in complex with ligand 32 -

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Basic information

Entry
Database: PDB / ID: 8g3x
TitleMBP-Mcl1 in complex with ligand 32
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 / cell fate determination / cellular homeostasis / cell envelope / 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 ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / cell envelope / 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 / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / 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 / response to cytokine / release of cytochrome c from mitochondria / intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of neuron apoptotic process / Signaling by ALK fusions and activated point mutants / channel activity / 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 / mitochondrion / nucleoplasm / nucleus / membrane / cytosol / cytoplasm
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-2 family ...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-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 / 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 / Periplasmic binding protein-like II / D-Maltodextrin-Binding Protein; domain 2 / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
alpha-maltose / Chem-YLF / 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: 1.46 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)59,19813
Polymers57,3111
Non-polymers1,88712
Water10,034557
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)99.400, 137.378, 38.491
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: obtained synthetically / 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.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-YLF / N-[(1'S,3aS,5R,15S,17S,19Z,21R,21aR)-6'-chloro-20-fluoro-21-{[(5S,9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]methyl}-21-methoxy-17-methyl-13,15-dioxo-2,3,3',3a,4,4',13,16,17,18,21,21a-dodecahydro-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'-naphthalen]-15-yl]-3-methoxy-1-methyl-1H-pyrazole-4-carboxamide


Mass: 924.519 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C46H59ClFN7O8S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 557 / 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: 2.25 Å3/Da / Density % sol: 45.49 %
Crystal growTemperature: 285 K / Method: vapor diffusion / pH: 7.5 / Details: 20.5% (w/v) PEG3350, 0.11M Mg formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Sep 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.46→80.53 Å / Num. obs: 92781 / % possible obs: 99.6 % / Redundancy: 8.3 % / CC1/2: 0.998 / Rpim(I) all: 0.02 / Rrim(I) all: 0.057 / Rsym value: 0.054 / Net I/σ(I): 16.4
Reflection shellResolution: 1.46→1.48 Å / Redundancy: 8.5 % / Mean I/σ(I) obs: 1.3 / Num. unique obs: 4566 / CC1/2: 0.795 / Rpim(I) all: 0.438 / Rrim(I) all: 1.304 / Rsym value: 1.226 / % possible all: 98.3

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Processing

Software
NameVersionClassification
REFMAC7.1.015refinement
autoPROC1.1.7data reduction
PHASER7.1.015phasing
Aimless0.7.7data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.46→80.53 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.969 / SU B: 1.807 / SU ML: 0.064 / Cross valid method: THROUGHOUT / ESU R: 0.073 / ESU R Free: 0.072 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2059 4829 5.2 %RANDOM
Rwork0.18232 ---
obs0.18356 87951 99.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.337 Å2
Baniso -1Baniso -2Baniso -3
1-1.06 Å2-0 Å20 Å2
2---1.55 Å20 Å2
3---0.49 Å2
Refinement stepCycle: LAST / Resolution: 1.46→80.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4042 0 127 557 4726
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0194477
X-RAY DIFFRACTIONr_bond_other_d0.0020.024267
X-RAY DIFFRACTIONr_angle_refined_deg1.3671.9826101
X-RAY DIFFRACTIONr_angle_other_deg0.94339853
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.25570
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.03824.715193
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.17215.181772
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6471520
X-RAY DIFFRACTIONr_chiral_restr0.0810.2665
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215137
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02992
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_it1.3012.5762205
X-RAY DIFFRACTIONr_mcbond_other1.3012.5762204
X-RAY DIFFRACTIONr_mcangle_it1.933.8632800
X-RAY DIFFRACTIONr_mcangle_other1.933.8632801
X-RAY DIFFRACTIONr_scbond_it1.8692.8562272
X-RAY DIFFRACTIONr_scbond_other1.8672.8562272
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.924.1783302
X-RAY DIFFRACTIONr_long_range_B_refined5.73822.9725781
X-RAY DIFFRACTIONr_long_range_B_other5.46221.9775478
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.46→1.495 Å
RfactorNum. reflection% reflection
Rfree0.346 339 -
Rwork0.334 6374 -
obs--98.58 %
Refinement TLS params.Method: refined / Origin x: -16.456 Å / Origin y: 54.931 Å / Origin z: -6.407 Å
111213212223313233
T0.0265 Å2-0.0038 Å2-0.0602 Å2-0.0336 Å20.0062 Å2--0.1658 Å2
L2.588 °21.0396 °2-1.6932 °2-4.652 °2-1.032 °2--4.1864 °2
S-0.0528 Å °-0.2567 Å °0.1894 Å °0.2386 Å °-0.1871 Å °-0.307 Å °-0.0567 Å °0.3153 Å °0.2399 Å °

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