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- PDB-4i80: Crystal structure of human menin in complex with a high-affinity ... -

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Basic information

Entry
Database: PDB / ID: 4i80
TitleCrystal structure of human menin in complex with a high-affinity macrocyclic peptidomimetics
Components
  • Menin
  • macrocyclic peptidomimetic
KeywordsTRANSCRIPTION/INHIBITOR / menin / MEN1 / MLL / macrocyclic peptidomimetic / TRANSCRIPTION / TRANSCRIPTION-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 / R-SMAD binding / cleavage furrow / MLL1 complex / negative regulation of cell cycle / RHO GTPases activate IQGAPs / negative regulation of osteoblast differentiation / response to UV / four-way junction DNA binding / transcription initiation-coupled chromatin remodeling / transcription repressor complex / negative regulation of protein phosphorylation / Deactivation of the beta-catenin transactivating complex / response to gamma radiation / phosphoprotein binding / Post-translational protein phosphorylation / 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 / negative regulation of cell population proliferation / endoplasmic reticulum lumen / 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 / cytoplasm / cytosol
Similarity search - Function
macrocyclic peptidomimetic / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.1 Å
AuthorsHuang, J. / Lei, M.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein-Protein Interaction.
Authors: Zhou, H. / Liu, L. / Huang, J. / Bernard, D. / Karatas, H. / Navarro, A. / Lei, M. / Wang, S.
History
DepositionDec 1, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2013Group: Derived calculations
Revision 1.2Jun 21, 2017Group: Database references / Source and taxonomy
Category: entity_src_gen / pdbx_entity_src_syn ...entity_src_gen / pdbx_entity_src_syn / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _pdbx_entity_src_syn.pdbx_beg_seq_num / _pdbx_entity_src_syn.pdbx_end_seq_num ..._pdbx_entity_src_syn.pdbx_beg_seq_num / _pdbx_entity_src_syn.pdbx_end_seq_num / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.ref_id
Revision 1.3Nov 15, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Menin
B: macrocyclic peptidomimetic


Theoretical massNumber of molelcules
Total (without water)62,1892
Polymers62,1892
Non-polymers00
Water00
1
A: Menin
B: macrocyclic peptidomimetic

A: Menin
B: macrocyclic peptidomimetic


Theoretical massNumber of molelcules
Total (without water)124,3774
Polymers124,3774
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_555-y,-x,-z+1/21
Buried area5810 Å2
ΔGint-30 kcal/mol
Surface area42280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.379, 141.379, 92.879
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Menin


Mass: 61061.234 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) / Strain (production host): BL21(DE3) / References: UniProt: O00255
#2: Protein/peptide macrocyclic peptidomimetic


Type: Peptide-like / Class: Inhibitor / Mass: 1127.384 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: chemically synthesized compound / Source: (synth.) synthetic (others) / References: macrocyclic peptidomimetic
Sequence detailsMENIN SEQUENCE (CHAIN A) IS MENIN ISOFORM 2 (UNP IDENTIFIER: O00255-2). THE SEQUENCE OF THIS ...MENIN SEQUENCE (CHAIN A) IS MENIN ISOFORM 2 (UNP IDENTIFIER: O00255-2). THE SEQUENCE OF THIS ISOFORM DIFFERS FROM THE CANONICAL SEQUENCE AS FOLLOWS: RESIDUES 149-153 ARE MISSING

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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: 3.73 Å3/Da / Density % sol: 67.04 %
Crystal growTemperature: 277 K / pH: 7
Details: 2.3 M NaCl, pH 7.0, vapor diffusion, sitting drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.97941
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 25, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97941 Å / Relative weight: 1
ReflectionResolution: 3.096→100 Å / Num. obs: 16363 / % possible obs: 92.4 % / Redundancy: 25.5 % / Rmerge(I) obs: 0.098 / Net I/σ(I): 11.2
Reflection shellResolution: 3.1→3.21 Å / Redundancy: 20.1 % / Rmerge(I) obs: 0.291 / % possible all: 73.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIX1.7_650refinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.1→44.71 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.38 / σ(F): 1.35 / Phase error: 29.4 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.245 1622 9.95 %
Rwork0.215 --
obs0.218 16307 92.2 %
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 79.2 Å2 / ksol: 0.35 e/Å3
Displacement parametersBiso mean: 107.76 Å2
Baniso -1Baniso -2Baniso -3
1--46.3287 Å2-0 Å20 Å2
2---46.3287 Å2-0 Å2
3---92.6574 Å2
Refinement stepCycle: LAST / Resolution: 3.1→44.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3893 0 0 0 3893
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0093983
X-RAY DIFFRACTIONf_angle_d1.2465403
X-RAY DIFFRACTIONf_dihedral_angle_d15.7171455
X-RAY DIFFRACTIONf_chiral_restr0.067600
X-RAY DIFFRACTIONf_plane_restr0.005694
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.096-3.18720.3571080.3024912X-RAY DIFFRACTION71
3.1872-3.290.388960.3034997X-RAY DIFFRACTION75
3.29-3.40760.31981090.2831042X-RAY DIFFRACTION81
3.4076-3.5440.25171190.26981160X-RAY DIFFRACTION87
3.544-3.70520.26881340.23671202X-RAY DIFFRACTION93
3.7052-3.90040.24641700.2121274X-RAY DIFFRACTION99
3.9004-4.14460.26581410.1961303X-RAY DIFFRACTION100
4.1446-4.46440.2221340.19111336X-RAY DIFFRACTION100
4.4644-4.91310.24161560.19441314X-RAY DIFFRACTION100
4.9131-5.62290.20671660.19581322X-RAY DIFFRACTION100
5.6229-7.07970.25691410.20351370X-RAY DIFFRACTION100
7.0797-44.71260.20831480.20031453X-RAY DIFFRACTION100

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