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- PDB-4og8: Human menin with bound inhibitor MIV-6R -

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Basic information

Entry
Database: PDB / ID: 4og8
TitleHuman menin with bound inhibitor MIV-6R
ComponentsMenin
KeywordsPROTEIN BINDING/INHIBITOR / PROTEIN BINDING-INHIBITOR complex
Function / homology
Function and homology information


Y-form DNA binding / negative regulation of telomerase activity / negative regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of JNK cascade / MLL1/2 complex / T-helper 2 cell differentiation / osteoblast development / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway ...Y-form DNA binding / negative regulation of telomerase activity / negative regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of JNK cascade / MLL1/2 complex / T-helper 2 cell differentiation / osteoblast development / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway / MLL1 complex / R-SMAD binding / cleavage furrow / negative regulation of cell cycle / RHO GTPases activate IQGAPs / negative regulation of osteoblast differentiation / four-way junction DNA binding / response to UV / transcription initiation-coupled chromatin remodeling / transcription repressor complex / negative regulation of protein phosphorylation / Deactivation of the beta-catenin transactivating complex / Post-translational protein phosphorylation / response to gamma radiation / phosphoprotein binding / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Formation of the beta-catenin:TCF transactivating complex / negative regulation of DNA-binding transcription factor activity / nuclear matrix / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / MAPK cascade / protein-macromolecule adaptor activity / double-stranded DNA binding / 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 / chromatin / regulation of transcription by RNA polymerase II / 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
Chem-2SF / 2-PHOSPHOGLYCOLIC ACID / TERT-BUTYL FORMATE / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.53 Å
AuthorsHe, S. / Senter, T.J. / Pollock, J.W. / Han, C. / Upadhyay, S.K. / Purohit, T. / Gogliotti, R.D. / Lindsley, C.W. / Cierpicki, T. / Stauffer, S.R. / Grembecka, J.
CitationJournal: J.Med.Chem. / Year: 2014
Title: High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein-Protein Interaction.
Authors: He, S. / Senter, T.J. / Pollock, J. / Han, C. / Upadhyay, S.K. / Purohit, T. / Gogliotti, R.D. / Lindsley, C.W. / Cierpicki, T. / Stauffer, S.R. / Grembecka, J.
History
DepositionJan 15, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 5, 2014Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,09512
Polymers54,6001
Non-polymers1,49511
Water7,728429
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.782, 80.224, 124.691
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Menin


Mass: 54600.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MEN1, SCG2 / Production host: Escherichia coli (E. coli) / References: UniProt: O00255

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Non-polymers , 7 types, 440 molecules

#2: Chemical ChemComp-TBF / TERT-BUTYL FORMATE / TERTIARY BUTOXY CARBONYL / Tert-Butyl formate


Mass: 102.132 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H10O2
#3: Chemical ChemComp-2SF / 4-(3-{4-[(R)-amino(cyclopentyl)phenylmethyl]piperidin-1-yl}propoxy)benzonitrile


Mass: 417.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H35N3O
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Chemical ChemComp-PGA / 2-PHOSPHOGLYCOLIC ACID


Mass: 156.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C2H5O6P
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 429 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsTHE CRYSTALLIZED SEQUENCE CORRESPONDS TO THE HUMAN MENIN ISOFORM 2

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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: 2.24 Å3/Da / Density % sol: 44.98 %
Crystal growTemperature: 283 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.2 M ammonium acetate, 0.1 M HEPES pH 7.5 and 25% w/v PEG 3,350. This solution was mixed 1:1 with 2.5mg/mL protein in 50mM Tris-HCl (pH 8.0), 50mM NaCl, and 1mM TCEP. Prior to data ...Details: 0.2 M ammonium acetate, 0.1 M HEPES pH 7.5 and 25% w/v PEG 3,350. This solution was mixed 1:1 with 2.5mg/mL protein in 50mM Tris-HCl (pH 8.0), 50mM NaCl, and 1mM TCEP. Prior to data collection, crystals were transferred into a cryo-solution containing 20% PEG550 MME and flash-frozen in liquid nitrogen, VAPOR DIFFUSION, SITTING DROP, temperature 283K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 5, 2013
RadiationMonochromator: C(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.53→41.68 Å / Num. all: 483441 / Num. obs: 73430 / Redundancy: 6.6 % / Rsym value: 0.069 / Net I/σ(I): 28.38

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.7.0032refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 4GPQ

4gpq


Resolution: 1.53→41.68 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.964 / SU B: 2.13 / SU ML: 0.04 / Cross valid method: THROUGHOUT / ESU R: 0.067 / ESU R Free: 0.068 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.17596 3693 5 %RANDOM
Rwork0.15115 ---
obs0.15237 69656 98.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.156 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å20 Å20 Å2
2---0.05 Å20 Å2
3---0.08 Å2
Refinement stepCycle: LAST / Resolution: 1.53→41.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3669 0 81 429 4179
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0193905
X-RAY DIFFRACTIONr_bond_other_d0.0040.023697
X-RAY DIFFRACTIONr_angle_refined_deg1.7351.9795299
X-RAY DIFFRACTIONr_angle_other_deg1.0613.0078490
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7115483
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.6823.943175
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.36315636
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0151524
X-RAY DIFFRACTIONr_chiral_restr0.120.2589
X-RAY DIFFRACTIONr_gen_planes_refined0.010.024418
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02907
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_it2.4911.581918
X-RAY DIFFRACTIONr_mcbond_other2.4911.5811918
X-RAY DIFFRACTIONr_mcangle_it3.2372.4472404
X-RAY DIFFRACTIONr_mcangle_other3.2372.4522405
X-RAY DIFFRACTIONr_scbond_it4.5442.6071987
X-RAY DIFFRACTIONr_scbond_other4.5442.6081987
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.523.6442895
X-RAY DIFFRACTIONr_long_range_B_refined8.1327.5644873
X-RAY DIFFRACTIONr_long_range_B_other8.1327.5754874
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.531→1.571 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.246 230 -
Rwork0.221 4816 -
obs--92.91 %
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)
11.9293-0.74-0.2831.80211.01782.2227-0.04180.0931-0.25690.0862-0.01230.1130.3845-0.1060.05410.1732-0.0237-0.01820.1397-0.02770.13994.558-10.294-1.185
21.4245-0.51190.18811.1603-0.16521.46590.04650.21780.0071-0.0362-0.03860.01260.10130.0168-0.00790.12640.0042-0.0150.1626-0.01330.082912.889-3.336-5.989
31.9257-0.70330.34141.2099-0.12022.3910.03680.0985-0.2423-0.0388-0.0124-0.06720.27530.1703-0.02440.16590.0261-0.01990.1491-0.02930.12830.468-10.72811.189
47.0894-10.14331.213720.34693.72535.322-0.05290.34520.7178-0.4646-0.2022-0.8918-0.50230.33460.25510.1656-0.05870.01830.20890.08910.27727.7399.129-1.074
50.82460.02470.28720.38920.24631.40330.05170.0804-0.0051-0.02070.0384-0.05110.1350.1333-0.09010.11620.0354-0.00960.1351-0.01060.090622.412-0.02910.293
61.4191-2.01080.42534.91530.77071.68160.04790.00270.2333-0.01460.028-0.45440.08690.258-0.07590.09020.0148-0.00110.14410.00190.129326.8667.38522.494
70.89840.00190.47750.4650.44351.07350.00650.03610.0556-0.0349-0.06540.07050.0279-0.08010.05890.10430.0045-0.00270.1217-0.0050.09996.2375.4198.856
80.118-0.0329-0.06491.23560.24870.40730.00460.02810.0019-0.046-0.04570.0768-0.0118-0.05640.04110.08440.0086-0.00450.1248-0.00780.09366.86622.74220.426
94.7583-2.2788-2.44222.2520.90812.251-0.1155-0.20160.02990.14240.1035-0.021-0.09890.15490.0120.1284-0.0169-0.02330.1365-0.01240.09510.03936.46527.726
102.76861.48761.17783.64360.32560.8349-0.25820.01660.3185-0.15760.10310.2343-0.2260.00390.15520.1753-0.0166-0.0610.1124-0.00240.121315.97538.59632.55
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 30
2X-RAY DIFFRACTION2A31 - 97
3X-RAY DIFFRACTION3A98 - 127
4X-RAY DIFFRACTION4A128 - 137
5X-RAY DIFFRACTION5A138 - 204
6X-RAY DIFFRACTION6A205 - 222
7X-RAY DIFFRACTION7A223 - 289
8X-RAY DIFFRACTION8A290 - 428
9X-RAY DIFFRACTION9A429 - 461
10X-RAY DIFFRACTION10A548 - 588

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