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- PDB-6u9k: MLL1 SET N3861I/Q3867L bound to inhibitor 18 (TC-5153) -

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Basic information

Entry
Database: PDB / ID: 6u9k
TitleMLL1 SET N3861I/Q3867L bound to inhibitor 18 (TC-5153)
ComponentsHistone-lysine N-methyltransferase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


protein-cysteine methyltransferase activity / response to potassium ion / [histone H3]-lysine4 N-methyltransferase / histone H3K4 monomethyltransferase activity / unmethylated CpG binding / histone H3K4 trimethyltransferase activity / negative regulation of DNA methylation-dependent heterochromatin formation / regulation of short-term neuronal synaptic plasticity / T-helper 2 cell differentiation / definitive hemopoiesis ...protein-cysteine methyltransferase activity / response to potassium ion / [histone H3]-lysine4 N-methyltransferase / histone H3K4 monomethyltransferase activity / unmethylated CpG binding / histone H3K4 trimethyltransferase activity / negative regulation of DNA methylation-dependent heterochromatin formation / regulation of short-term neuronal synaptic plasticity / T-helper 2 cell differentiation / definitive hemopoiesis / histone H3K4 methyltransferase activity / embryonic hemopoiesis / exploration behavior / anterior/posterior pattern specification / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / minor groove of adenine-thymine-rich DNA binding / membrane depolarization / MLL1 complex / negative regulation of fibroblast proliferation / homeostasis of number of cells within a tissue / spleen development / transcription initiation-coupled chromatin remodeling / cellular response to transforming growth factor beta stimulus / Transferases; Transferring one-carbon groups; Methyltransferases / post-embryonic development / circadian regulation of gene expression / lysine-acetylated histone binding / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / visual learning / protein modification process / PKMTs methylate histone lysines / Transcriptional regulation of granulopoiesis / RUNX1 regulates transcription of genes involved in differentiation of HSCs / fibroblast proliferation / methylation / protein-containing complex assembly / apoptotic process / chromatin binding / positive regulation of DNA-templated transcription / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytosol
Similarity search - Function
KMT2A, ePHD domain / KMT2A, PHD domain 1 / KMT2A, PHD domain 2 / KMT2A, PHD domain 3 / Methyltransferase, trithorax / : / FY-rich, N-terminal / F/Y-rich N-terminus / PHD-like zinc-binding domain / FYR domain FYRN motif profile. ...KMT2A, ePHD domain / KMT2A, PHD domain 1 / KMT2A, PHD domain 2 / KMT2A, PHD domain 3 / Methyltransferase, trithorax / : / FY-rich, N-terminal / F/Y-rich N-terminus / PHD-like zinc-binding domain / FYR domain FYRN motif profile. / "FY-rich" domain, N-terminal region / FY-rich, C-terminal / F/Y rich C-terminus / FYR domain FYRC motif profile. / "FY-rich" domain, C-terminal region / CXXC zinc finger domain / Zinc finger, CXXC-type / Zinc finger CXXC-type profile. / Cysteine-rich motif following a subset of SET domains / Post-SET domain / Post-SET domain profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / Extended PHD (ePHD) domain / Extended PHD (ePHD) domain profile. / SET domain profile. / SET domain / PHD-finger / Zinc finger PHD-type signature. / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-Q2V / cDNA FLJ56846, highly similar to Zinc finger protein HRX / Histone-lysine N-methyltransferase 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsPetrunak, E.M. / Stuckey, J.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of Potent Small-Molecule Inhibitors of MLL Methyltransferase.
Authors: Chern, T.R. / Liu, L. / Petrunak, E. / Stuckey, J.A. / Wang, M. / Bernard, D. / Zhou, H. / Lee, S. / Dou, Y. / Wang, S.
History
DepositionSep 9, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2020Provider: 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: Histone-lysine N-methyltransferase
B: Histone-lysine N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9717
Polymers36,4862
Non-polymers1,4845
Water3,009167
1
A: Histone-lysine N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,9393
Polymers18,2431
Non-polymers6962
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone-lysine N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0314
Polymers18,2431
Non-polymers7883
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.949, 54.949, 104.895
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number145
Space group name H-MP32

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Components

#1: Protein Histone-lysine N-methyltransferase


Mass: 18243.195 Da / Num. of mol.: 2 / Mutation: N3861I, Q3867L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
References: UniProt: B4DIJ7, UniProt: Q03164*PLUS, histone-lysine N-methyltransferase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-Q2V / 5'-([(3S)-3-amino-3-carboxypropyl]{[1-(3,3-diphenylpropyl)azetidin-3-yl]methyl}amino)-5'-deoxyadenosine


Mass: 630.737 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C33H42N8O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 167 / 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: 2.63 Å3/Da / Density % sol: 53.29 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 2.2 M Sodium Malonate pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9786 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Feb 7, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 23928 / % possible obs: 100 % / Redundancy: 7.8 % / Rsym value: 0.05 / Net I/σ(I): 10
Reflection shellResolution: 2→2.03 Å / Mean I/σ(I) obs: 2 / Num. unique obs: 23928 / Rsym value: 0.559

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5F5E

5f5e


Resolution: 2→43.34 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.911 / SU R Cruickshank DPI: 0.181 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.178 / SU Rfree Blow DPI: 0.158 / SU Rfree Cruickshank DPI: 0.159
RfactorNum. reflection% reflectionSelection details
Rfree0.244 1203 5.03 %RANDOM
Rwork0.207 ---
obs0.209 23928 99.9 %-
Displacement parametersBiso max: 138.49 Å2 / Biso mean: 35.25 Å2 / Biso min: 7.79 Å2
Baniso -1Baniso -2Baniso -3
1--0.1235 Å20 Å20 Å2
2---0.1235 Å20 Å2
3---0.247 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: final / Resolution: 2→43.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2293 0 192 167 2652
Biso mean--31.42 37.57 -
Num. residues----298
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d861SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes489HARMONIC5
X-RAY DIFFRACTIONt_it2538HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion322SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance8HARMONIC1
X-RAY DIFFRACTIONt_utility_angle12HARMONIC1
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3032SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2538HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3505HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion3.17
X-RAY DIFFRACTIONt_other_torsion16.1
LS refinement shellResolution: 2→2.01 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2583 29 6.05 %
Rwork0.2327 450 -
all0.2343 479 -
obs--97.46 %
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)
11.5985-1.5265-0.37030.4922-1.812300.0729-0.1180.0481-0.04410.005-0.135-0.38510.2089-0.07790.05310.13830.0097-0.0042-0.0916-0.064319.12025.1943-2.3187
24.2511-1.8326-1.74997.9778-1.89968.43020.473-0.01290.2665-0.8355-0.4554-0.43050.11870.4857-0.01760.19340.11840.0246-0.02030.02220.05893.475514.91811.6925
32.99220.3868-1.09143.3045-0.82222.60050.0762-0.2268-0.4593-0.5096-0.30860.26730.31790.0840.2324-0.10030.0744-0.0223-0.18770.0082-0.10852.0709-0.130910.234
43.7149-4.9838-1.51038.1096-1.10984.50370.44810.20570.0617-0.9709-0.4645-0.31980.64560.30460.01650.21120.1997-0.048-0.1751-0.0083-0.13935.02586.8909-1.6661
57.2355.263.99465.50545.338200.2797-0.17090.0147-0.2361-0.0133-0.10710.1384-0.3346-0.26640.0363-0.0143-0.14490.0456-0.023-0.058-13.11332.5988-1.7236
62.9535-2.15780.643-1.3855-1.36130-0.00850.0694-0.0771-0.12930.14510.12480.1321-0.5178-0.13660.20480.1054-0.0748-0.02270.0560.0513-15.165319.1885-8.2945
78.3182-3.3388-3.43014.41470.14916.4633-0.3569-0.09950.14310.35080.46790.15690.0133-0.1213-0.1111-0.04990.1012-0.0155-0.103-0.0023-0.0776-13.70640.0682-13.4111
84.9846-0.4183-2.85253.6359-0.33812.5859-0.6323-0.2337-0.07830.21470.4062-0.41070.23420.25170.22610.00950.0874-0.0217-0.0577-0.0185-0.0099-2.206830.4918-18.198
92.6375-5.1571-1.85489.95210.21454.1973-0.5704-0.434-0.18540.7290.51690.2260.74790.36620.05350.030.2832-0.0421-0.1309-0.0381-0.2417-7.020729.2636-7.8399
108.12725.20836.94763.305-1.61350-0.0402-0.0642-0.1179-0.11030.32620.0385-0.2040.4059-0.2859-0.03740.0164-0.0870.0851-0.1591-0.0684.568244.6622-6.946
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|3813 - 3823}A3813 - 3823
2X-RAY DIFFRACTION2{A|3824 - 3855}A3824 - 3855
3X-RAY DIFFRACTION3{A|3856 - 3919}A3856 - 3919
4X-RAY DIFFRACTION4{A|3920 - 3945}A3920 - 3945
5X-RAY DIFFRACTION5{A|3946 - 3968}A3946 - 3968
6X-RAY DIFFRACTION6{B|3814 - 3826}B3814 - 3826
7X-RAY DIFFRACTION7{B|3827 - 3847}B3827 - 3847
8X-RAY DIFFRACTION8{B|3848 - 3914}B3848 - 3914
9X-RAY DIFFRACTION9{B|3915 - 3946}B3915 - 3946
10X-RAY DIFFRACTION10{B|3954 - 3969}B3954 - 3969

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