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- PDB-9c94: Crystal structure of menin in complex with inhibitor compound 20 -

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Basic information

Entry
Database: PDB / ID: 9c94
TitleCrystal structure of menin in complex with inhibitor compound 20
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: 1.98 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)115,0664
Polymers114,0212
Non-polymers1,0452
Water10,971609
1
A: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5332
Polymers57,0101
Non-polymers5231
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5332
Polymers57,0101
Non-polymers5231
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.758, 87.476, 194.610
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

#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
#2: Chemical ChemComp-A1AVG / {5-fluoro-2-[(5-{7-[(1-methylcyclopropyl)methyl]-2,7-diazaspiro[3.5]nonan-2-yl}-1,2,4-triazin-6-yl)oxy]phenyl}[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]methanone


Mass: 522.614 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H35FN6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 609 / Source method: isolated from a natural source / Formula: H2O
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: 2.12 Å3/Da / Density % sol: 41.94 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 22% PEG 3350, 0.1M HEPES pH6.9, 0.2M Na 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 6, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.98→97.31 Å / Num. obs: 37789 / % possible obs: 98.9 % / Redundancy: 5.7 % / Biso Wilson estimate: 28.73 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.132 / Rpim(I) all: 0.084 / Rrim(I) all: 0.145 / Net I/σ(I): 8.9
Reflection shellResolution: 1.98→2.09 Å / Redundancy: 5.5 % / Rmerge(I) obs: 0.837 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 9907 / CC1/2: 0.707 / Rpim(I) all: 0.394 / Rrim(I) all: 0.927 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
CrysalisProdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.98→54.49 Å / SU ML: 0.2315 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 19.8836
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2117 3426 5.06 %
Rwork0.178 64270 -
obs0.1797 37789 98.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.85 Å2
Refinement stepCycle: LAST / Resolution: 1.98→54.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7425 0 76 609 8110
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0047741
X-RAY DIFFRACTIONf_angle_d0.764110532
X-RAY DIFFRACTIONf_chiral_restr0.04471153
X-RAY DIFFRACTIONf_plane_restr0.0071347
X-RAY DIFFRACTIONf_dihedral_angle_d18.53112843
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.98-2.010.28141290.24812712X-RAY DIFFRACTION100
2.01-2.040.27941470.24232664X-RAY DIFFRACTION100
2.04-2.070.27081490.2272639X-RAY DIFFRACTION99.93
2.07-2.10.28541420.22872687X-RAY DIFFRACTION100
2.1-2.140.28391580.20682645X-RAY DIFFRACTION100
2.14-2.180.25781380.19682694X-RAY DIFFRACTION99.93
2.18-2.220.24731400.19152640X-RAY DIFFRACTION100
2.22-2.270.2089990.19362036X-RAY DIFFRACTION75.04
2.27-2.320.2751330.18992672X-RAY DIFFRACTION100
2.32-2.370.22491510.18742715X-RAY DIFFRACTION99.97
2.37-2.430.24131430.19122651X-RAY DIFFRACTION100
2.43-2.490.20971240.1912692X-RAY DIFFRACTION100
2.49-2.570.23641500.19142695X-RAY DIFFRACTION100
2.57-2.650.24761380.18232691X-RAY DIFFRACTION99.96
2.65-2.750.22651650.19432692X-RAY DIFFRACTION100
2.75-2.860.2591360.19662678X-RAY DIFFRACTION100
2.86-2.990.21621390.20082735X-RAY DIFFRACTION99.93
2.99-3.140.22531680.18692674X-RAY DIFFRACTION99.93
3.14-3.340.23681350.17422731X-RAY DIFFRACTION99.93
3.34-3.60.17161380.15952720X-RAY DIFFRACTION99.86
3.6-3.960.1731560.14942725X-RAY DIFFRACTION99.83
3.96-4.530.15561390.14032759X-RAY DIFFRACTION99.9
4.53-5.710.18361680.16012784X-RAY DIFFRACTION99.93
5.71-54.490.18631410.17182939X-RAY DIFFRACTION99.42
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)
11.31963634866-0.893591938833-0.172297437171.855731710840.398227426550.4499632160870.0813028741830.141440482126-0.270218589882-0.15145695166-0.08381128687080.1998384883810.05430664902070.0276207326843-0.003692702941740.1865924536750.0267493975914-0.03151322725930.210003500747-0.01268087202310.176311864336-14.5236634731-12.114746965-24.0916760564
20.83972595747-0.1054862715870.2134869884251.61463176295-0.5653988247180.6701508680270.001683706479560.0328168376582-0.0441069634895-0.0265104349870.01914800241340.0269038701920.03509917158920.00388832975122-0.02077570732540.1254283805390.005602530895050.02440082245610.175819465831-0.008545974466920.1301180921529.3479868927916.8798884258-21.1950013189
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain 'A' and resid 2 through 583)AA2 - 5831 - 464
22(chain 'B' and resid 2 through 582)BD2 - 5821 - 474

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