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- PDB-8ig0: Crystal structure of menin in complex with DS-1594b -

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Basic information

Entry
Database: PDB / ID: 8ig0
TitleCrystal structure of menin in complex with DS-1594b
ComponentsMenin
KeywordsTRANSCRIPTION/INHIBITOR / leukemia / TRANSCRIPTION-INHIBITOR COMPLEX
Function / homology
Function and homology information


Y-form DNA binding / negative regulation of cyclin-dependent protein serine/threonine kinase activity / MLL1/2 complex / negative regulation of JNK cascade / osteoblast development / T-helper 2 cell differentiation / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway / R-SMAD binding ...Y-form DNA binding / negative regulation of cyclin-dependent protein serine/threonine kinase activity / MLL1/2 complex / negative regulation of JNK cascade / osteoblast development / T-helper 2 cell differentiation / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway / R-SMAD binding / cleavage furrow / MLL1 complex / negative regulation of cell cycle / negative regulation of protein phosphorylation / negative regulation of osteoblast differentiation / RHO GTPases activate IQGAPs / response to UV / four-way junction DNA binding / transcription repressor complex / transcription initiation-coupled chromatin remodeling / response to gamma radiation / negative regulation of DNA-binding transcription factor activity / phosphoprotein binding / Post-translational protein phosphorylation / Deactivation of the beta-catenin transactivating complex / Formation of the beta-catenin:TCF transactivating complex / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / nuclear matrix / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / MAPK cascade / double-stranded DNA binding / protein-macromolecule adaptor activity / chromosome, telomeric region / transcription cis-regulatory region binding / endoplasmic reticulum lumen / negative regulation of cell population proliferation / DNA repair / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsSuzuki, M. / Yoneyama, T. / Imai, E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cancer Cell Int / Year: 2023
Title: A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1.
Authors: Numata, M. / Haginoya, N. / Shiroishi, M. / Hirata, T. / Sato-Otsubo, A. / Yoshikawa, K. / Takata, Y. / Nagase, R. / Kashimoto, Y. / Suzuki, M. / Schulte, N. / Polier, G. / Kurimoto, A. / ...Authors: Numata, M. / Haginoya, N. / Shiroishi, M. / Hirata, T. / Sato-Otsubo, A. / Yoshikawa, K. / Takata, Y. / Nagase, R. / Kashimoto, Y. / Suzuki, M. / Schulte, N. / Polier, G. / Kurimoto, A. / Tomoe, Y. / Toyota, A. / Yoneyama, T. / Imai, E. / Watanabe, K. / Hamada, T. / Kanada, R. / Watanabe, J. / Kagoshima, Y. / Tokumaru, E. / Murata, K. / Baba, T. / Shinozaki, T. / Ohtsuka, M. / Goto, K. / Karibe, T. / Deguchi, T. / Gocho, Y. / Yoshida, M. / Tomizawa, D. / Kato, M. / Tsutsumi, S. / Kitagawa, M. / Abe, Y.
History
DepositionFeb 20, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _pdbx_initial_refinement_model.type

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Menin
B: Menin
C: Menin
D: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)247,03216
Polymers244,4214
Non-polymers2,61112
Water2,558142
1
A: Menin
B: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,5168
Polymers122,2112
Non-polymers1,3066
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2120 Å2
ΔGint-9 kcal/mol
Surface area40180 Å2
MethodPISA
2
C: Menin
D: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,5168
Polymers122,2112
Non-polymers1,3066
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2250 Å2
ΔGint-9 kcal/mol
Surface area40070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.576, 70.151, 144.426
Angle α, β, γ (deg.)90.000, 91.470, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Menin


Mass: 61105.352 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: The construct is a deletion mutant of menin isoform 2 (delta 460-519).
Source: (gene. exp.) Homo sapiens (human) / Gene: MEN1, SCG2 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2 (DE3) / References: UniProt: O00255
#2: Chemical
ChemComp-7IX / (1R,2S,4R)-4-[[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methylamino]-2-[methyl-[6-[2,2,2-tris(fluoranyl)ethyl]thieno[2,3-d]pyrimidin-4-yl]amino]cyclopentan-1-ol


Mass: 574.618 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H29F3N6O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 4 / Source method: obtained synthetically
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 142 / 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: 2.94 Å3/Da / Density % sol: 58.1 %
Crystal growTemperature: 283 K / Method: vapor diffusion, sitting drop / pH: 6.4
Details: 0.1 M Na Cacodylate HCl, pH 6.4/ 1.5 M NaOAc/ 20 mM BaCl2. Complex crystal was prepared with soaking method.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-1A / Wavelength: 1.07 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Mar 8, 2021
RadiationMonochromator: Si(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07 Å / Relative weight: 1
ReflectionResolution: 2.6→49.82 Å / Num. obs: 87588 / % possible obs: 99.8 % / Redundancy: 3.3 % / CC1/2: 0.997 / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.053 / Rrim(I) all: 0.099 / Net I/σ(I): 3.6 / Num. measured all: 289542 / Scaling rejects: 7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.6-2.653.11.2731370543710.5470.8321.5260.298.8
14-49.822.90.02817696070.9910.020.03518.797.4

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSMarch 1, 2015data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→25 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.918 / SU B: 21.646 / SU ML: 0.393 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.455 / ESU R Free: 0.3 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2661 4393 5 %RANDOM
Rwork0.212 ---
obs0.2147 83083 99.63 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 182.18 Å2 / Biso mean: 63.327 Å2 / Biso min: 6.31 Å2
Baniso -1Baniso -2Baniso -3
1--3.98 Å20 Å20.51 Å2
2--7.72 Å20 Å2
3----3.76 Å2
Refinement stepCycle: final / Resolution: 2.6→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14717 0 180 142 15039
Biso mean--48.39 47.62 -
Num. residues----1944
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.01215255
X-RAY DIFFRACTIONr_angle_refined_deg1.1771.64420815
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.24451932
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.68321.963703
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.042152237
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6761583
X-RAY DIFFRACTIONr_chiral_restr0.0810.21990
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211617
LS refinement shellResolution: 2.6→2.69 Å / Rfactor Rfree error: 0 / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.385 409 -
Rwork0.386 8010 -
all-8419 -
obs--99.25 %

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