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- PDB-6pkc: Inhibition of Human Menin by VTP-50469 -

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Basic information

Entry
Database: PDB / ID: 6pkc
TitleInhibition of Human Menin by VTP-50469
ComponentsMenin,Menin
KeywordsTRANSCRIPTION / Human Menin / Inhibitor Complex / VTP-50469
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: 1.9 Å
AuthorsMcKeever, B.M. / Chen, G. / Van Orton, R.
CitationJournal: Cancer Cell / Year: 2019
Title: A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia.
Authors: Krivtsov, A.V. / Evans, K. / Gadrey, J.Y. / Eschle, B.K. / Hatton, C. / Uckelmann, H.J. / Ross, K.N. / Perner, F. / Olsen, S.N. / Pritchard, T. / McDermott, L. / Jones, C.D. / Jing, D. / ...Authors: Krivtsov, A.V. / Evans, K. / Gadrey, J.Y. / Eschle, B.K. / Hatton, C. / Uckelmann, H.J. / Ross, K.N. / Perner, F. / Olsen, S.N. / Pritchard, T. / McDermott, L. / Jones, C.D. / Jing, D. / Braytee, A. / Chacon, D. / Earley, E. / McKeever, B.M. / Claremon, D. / Gifford, A.J. / Lee, H.J. / Teicher, B.A. / Pimanda, J.E. / Beck, D. / Perry, J.A. / Smith, M.A. / McGeehan, G.M. / Lock, R.B. / Armstrong, S.A.
History
DepositionJun 29, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Menin,Menin
B: Menin,Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,9964
Polymers109,7342
Non-polymers1,2622
Water10,305572
1
A: Menin,Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,4982
Polymers54,8671
Non-polymers6311
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Menin,Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,4982
Polymers54,8671
Non-polymers6311
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.970, 86.080, 202.040
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A2 - 583
2010B2 - 583

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Components

#1: Protein Menin,Menin


Mass: 54867.188 Da / Num. of mol.: 2 / Mutation: A5T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MEN1, SCG2 / Variant: 2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O00255
#2: Chemical ChemComp-OP4 / 5-fluoro-2-({4-[7-({trans-4-[(methylsulfonyl)amino]cyclohexyl}methyl)-2,7-diazaspiro[3.5]nonan-2-yl]pyrimidin-5-yl}oxy)-N,N-di(propan-2-yl)benzamide


Mass: 630.817 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H47FN6O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 572 / 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: 2.34 Å3/Da / Density % sol: 47.36 % / Description: Orthorhombic prisms
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 14%(w/v) PEG3350 0.2M Potassium thiocyanate 0.1M MES pH=6.0 15%(v/v) Ethylene glycol
PH range: 5.8 - 6.2 / Temp details: +/- 0.2'K

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: N2 cryostream / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 18, 2016 / Details: Mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→58.97 Å / Num. obs: 81943 / % possible obs: 99.9 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.052 / Net I/σ(I): 19.9
Reflection shellResolution: 1.9→1.949 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.3 / Num. unique obs: 5650 / % possible all: 99.97

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4GPQ

4gpq


Resolution: 1.9→48.65 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.943 / SU B: 2.82 / SU ML: 0.083 / Cross valid method: THROUGHOUT / ESU R: 0.138 / ESU R Free: 0.129 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20642 4146 5.1 %RANDOM
Rwork0.16848 ---
obs0.17036 77796 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 29.434 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å20 Å2
2---0.03 Å20 Å2
3---0.05 Å2
Refinement stepCycle: final / Resolution: 1.9→48.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7310 0 88 572 7970
Biso mean--18.82 35.1 -
Num. residues----923
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0197730
X-RAY DIFFRACTIONr_bond_other_d0.0090.027370
X-RAY DIFFRACTIONr_angle_refined_deg2.0061.97510518
X-RAY DIFFRACTIONr_angle_other_deg1.547316935
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6825954
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.29323.561351
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.765151278
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1071555
X-RAY DIFFRACTIONr_chiral_restr0.1210.21162
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0218763
X-RAY DIFFRACTIONr_gen_planes_other0.0080.021804
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_it3.0882.6983789
X-RAY DIFFRACTIONr_mcbond_other3.0872.6963788
X-RAY DIFFRACTIONr_mcangle_it4.454.0154756
X-RAY DIFFRACTIONr_mcangle_other4.454.0184753
X-RAY DIFFRACTIONr_scbond_it3.8823.0153941
X-RAY DIFFRACTIONr_scbond_other3.8813.0153942
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.0144.3695759
X-RAY DIFFRACTIONr_long_range_B_refined8.17321.4889276
X-RAY DIFFRACTIONr_long_range_B_other8.13821.2539082
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 56876 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.1 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.226 311 -
Rwork0.187 5650 -
obs--99.97 %

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