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- PDB-9c93: Crystal structure of menin in complex with inhibitor compound 26 -

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Basic information

Entry
Database: PDB / ID: 9c93
TitleCrystal structure of menin in complex with inhibitor compound 26
ComponentsMenin
KeywordsPROTEIN BINDING/INHIBITOR / PROTEIN BINDING / PROTEIN BINDING-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 / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsBester, S.M. / Wu, W.-I. / Mou, T.-C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2025
Title: Design of Potent Menin-KMT2A Interaction Inhibitors with Improved In Vitro ADME Properties and Reduced hERG Affinity.
Authors: Chapsal, B.D. / Kimbrough, J.R. / Bester, S.M. / Bergstrom, A. / Backos, D.S. / Campos, B. / McDonald, M.G. / Abrahamsen, R. / Allen, A.C. / Doerner Barbour, P.M. / Bettendorf, T. / Boys, M. ...Authors: Chapsal, B.D. / Kimbrough, J.R. / Bester, S.M. / Bergstrom, A. / Backos, D.S. / Campos, B. / McDonald, M.G. / Abrahamsen, R. / Allen, A.C. / Doerner Barbour, P.M. / Bettendorf, T. / Boys, M.L. / Brown, K. / Chicarelli, M.J. / Cook, A.W. / Crooks, A.L. / Cruz, C.L. / Dahlke, J.R. / Eide, A. / Fell, J.B. / Fulton, J.L. / Gargus, M. / Gaudino, J.J. / Guarnieri, A.L. / Hansen, E.P. / Holt, M.C. / Kahn, D.R. / Laird, E.R. / Larsen, P.D. / Linwood, R. / Martinson, M.C. / McCown, J. / Mejia, M.J. / Moreno, D.A. / Mou, T.C. / Newhouse, B. / O'Leary, J.M. / Rodriguez, M.E. / Singh, A. / Sinik, L. / Strand, K.A. / Touney, E.E. / Wollenberg, L.A. / Wong, J. / Zhou, Y. / Fischer, J.P. / Allen, S.
History
DepositionJun 13, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 15, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 5, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Menin
B: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,4198
Polymers114,0212
Non-polymers1,3986
Water12,358686
1
A: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5423
Polymers57,0101
Non-polymers5322
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,8775
Polymers57,0101
Non-polymers8664
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.559, 87.291, 194.974
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Menin


Mass: 57010.496 Da / Num. of mol.: 2 / Mutation: A5T
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 , 5 types, 692 molecules

#2: Chemical ChemComp-A1AVF / (1R,5R)-2-({5-fluoro-2-[(5-{7-[(1-methylcyclopropyl)methyl]-2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]phenyl}methyl)-2-azabicyclo[3.1.0]hexan-3-one


Mass: 492.588 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33FN6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K
#4: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 686 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.11 Å3/Da / Density % sol: 41.72 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 18% PEG 3350, 0.1M HEPES pH6.9, 0.2M K Thiocyanate, 4% Isopropanol, 1% Tacsimate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: Oct 28, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.85→22.38 Å / Num. obs: 82556 / % possible obs: 99 % / Redundancy: 5.5 % / Biso Wilson estimate: 17.68 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.046 / Rrim(I) all: 0.113 / Net I/σ(I): 11.5
Reflection shellResolution: 1.85→1.89 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.733 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 14869 / CC1/2: 0.54 / Rpim(I) all: 0.449 / Rrim(I) all: 0.918 / % possible all: 88.1

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
CrysalisProdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→22.38 Å / SU ML: 0.1913 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 22.045
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2247 7767 5 %
Rwork0.1797 147563 -
obs0.1819 82556 97.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.92 Å2
Refinement stepCycle: LAST / Resolution: 1.85→22.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7341 0 94 686 8121
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00577662
X-RAY DIFFRACTIONf_angle_d0.857710422
X-RAY DIFFRACTIONf_chiral_restr0.04571144
X-RAY DIFFRACTIONf_plane_restr0.00751325
X-RAY DIFFRACTIONf_dihedral_angle_d16.57261066
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.870.3112080.28883956X-RAY DIFFRACTION78.14
1.87-1.890.32432350.27184531X-RAY DIFFRACTION89.42
1.89-1.920.32562530.26854738X-RAY DIFFRACTION95.18
1.92-1.940.33242600.26314874X-RAY DIFFRACTION95.46
1.94-1.970.29942490.25554836X-RAY DIFFRACTION95.83
1.97-1.990.27722510.24034814X-RAY DIFFRACTION96.6
1.99-2.020.31152600.24224948X-RAY DIFFRACTION97.02
2.02-2.050.24332570.22334854X-RAY DIFFRACTION97.43
2.05-2.080.27012610.2174984X-RAY DIFFRACTION97.58
2.08-2.120.25662560.20634878X-RAY DIFFRACTION97.96
2.12-2.150.25252550.19844876X-RAY DIFFRACTION98.09
2.15-2.190.24382730.19085088X-RAY DIFFRACTION99.44
2.19-2.240.23022680.18535007X-RAY DIFFRACTION99.66
2.24-2.280.2282650.18045029X-RAY DIFFRACTION99.53
2.28-2.330.24372630.17914990X-RAY DIFFRACTION99.56
2.33-2.380.23512690.17175033X-RAY DIFFRACTION99.61
2.38-2.440.21332640.17894985X-RAY DIFFRACTION99.45
2.44-2.510.22592690.17675023X-RAY DIFFRACTION99.34
2.51-2.580.22892660.17835013X-RAY DIFFRACTION99.49
2.58-2.670.23092680.17925019X-RAY DIFFRACTION99.6
2.67-2.760.24072610.18615001X-RAY DIFFRACTION99.58
2.76-2.870.22252600.18295029X-RAY DIFFRACTION99.66
2.87-30.21052640.17135038X-RAY DIFFRACTION99.76
3-3.160.2282640.17185028X-RAY DIFFRACTION99.83
3.16-3.360.1992660.16695046X-RAY DIFFRACTION99.87
3.36-3.620.18262630.1515034X-RAY DIFFRACTION100
3.62-3.980.16632640.14085047X-RAY DIFFRACTION99.98
3.98-4.550.1822600.13545023X-RAY DIFFRACTION99.83
4.55-5.720.21842540.15935008X-RAY DIFFRACTION99.17
5.72-22.380.1912610.16544833X-RAY DIFFRACTION96.13

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