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- PDB-6u9r: MLL1 SET N3861I/Q3867L bound to inhibitor 12 (TC-5140) -

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Basic information

Entry
Database: PDB / ID: 6u9r
TitleMLL1 SET N3861I/Q3867L bound to inhibitor 12 (TC-5140)
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-Q2P / 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: 2.1 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)37,7396
Polymers36,4862
Non-polymers1,2534
Water2,630146
1
A: Histone-lysine N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,8703
Polymers18,2431
Non-polymers6262
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone-lysine N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,8703
Polymers18,2431
Non-polymers6262
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.692, 54.692, 105.530
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-Q2P / 5'-{[(3S)-3-amino-3-carboxypropyl]({1-[(3-chlorophenyl)methyl]azetidin-3-yl}methyl)amino}-5'-deoxyadenosine


Mass: 561.033 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H33ClN8O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 2.64 Å3/Da / Density % sol: 53.41 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 2.1 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: 2.1→50 Å / Num. obs: 20546 / % possible obs: 100 % / Redundancy: 8.7 % / Rsym value: 0.066 / Net I/σ(I): 10
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 8.8 % / Mean I/σ(I) obs: 2 / Num. unique obs: 20546 / Rsym value: 0.559 / % possible all: 100

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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: 2.1→21.61 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.874 / SU R Cruickshank DPI: 0.219 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.214 / SU Rfree Blow DPI: 0.183 / SU Rfree Cruickshank DPI: 0.185
RfactorNum. reflection% reflectionSelection details
Rfree0.255 998 4.86 %RANDOM
Rwork0.214 ---
obs0.216 20546 100 %-
Displacement parametersBiso max: 137.31 Å2 / Biso mean: 34.7 Å2 / Biso min: 7.42 Å2
Baniso -1Baniso -2Baniso -3
1-0.0145 Å20 Å20 Å2
2--0.0145 Å20 Å2
3----0.029 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.1→21.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2264 0 146 146 2556
Biso mean--20.84 33.2 -
Num. residues----297
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d832SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes460HARMONIC5
X-RAY DIFFRACTIONt_it2462HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion320SEMIHARMONIC5
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_contact2880SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2462HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3386HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion3.06
X-RAY DIFFRACTIONt_other_torsion16.7
LS refinement shellResolution: 2.1→2.12 Å / Rfactor Rfree error: 0 / Total num. of bins used: 49
RfactorNum. reflection% reflection
Rfree0.3296 12 2.86 %
Rwork0.2262 408 -
all0.2289 420 -
obs--98.37 %
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)
1-0.9203-0.0694-0.92483.0011-1.52900.0026-0.0987-0.01850.0523-0.0412-0.0954-0.18840.14970.03860.15210.177-0.0008-0.0031-0.0914-0.035518.50515.5166-4.2609
22.3704-2.1794-0.206210.3435-2.21167.55960.4770.16420.4444-0.8933-0.4154-0.43110.41490.3078-0.06170.13850.17220.0245-0.1310.0254-0.03573.416914.94630.3049
34.08390.4875-1.3515.5541-1.70720.67950.0912-0.3106-0.5196-0.7376-0.32370.30610.25360.0610.2325-0.09320.0982-0.0185-0.1583-0.0026-0.07521.5561-0.08429.6142
42.2206-4.0172-2.75047.2541-1.42497.22070.32740.23120.0542-0.9908-0.3575-0.19170.69770.22940.03010.2610.2476-0.0466-0.26710.0116-0.14725.00685.5551-2.6762
54.95351.14183.9712-0.19695.0340.0867-0.12850.0160.06220.04920.1464-0.0310.1461-0.0526-0.01790.11030.0197-0.1198-0.0073-0.0623-0.1046-13.96293.2218-3.8864
61.6954-0.7824-0.9421-0.5904-0.912100.0429-0.1468-0.01680.0010.0630.02290.198-0.2751-0.10590.18490.11010.0736-0.12120.08620.0983-15.759520.8887-10.4292
78.6241-4.6162-4.12596.3361.20216.32-0.2107-0.25610.33270.37020.41070.0141-0.12120.2129-0.2001-0.02520.1267-0.0222-0.1132-0.0054-0.0858-13.189940.605-14.859
85.5126-0.4964-2.51514.4968-0.4150.9682-0.6698-0.2892-0.07870.20680.4604-0.45280.14730.2350.2094-0.03810.088-0.0352-0.1648-0.0023-0.0766-2.223930.3664-20.1692
92.9835-4.6276-1.95897.0799-1.72494.5553-0.5486-0.4936-0.16080.65160.57320.16980.65060.2863-0.02460.14580.3613-0.0142-0.0865-0.0265-0.1767-6.970729.0799-9.1562
104.96342.78666.31961.56330.896700.1145-0.1316-0.0929-0.17870.0573-0.01170.05520.1387-0.17170.04750.0406-0.1040.0684-0.0767-0.1194.16145.2316-7.9531
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 - 3916}A3856 - 3916
4X-RAY DIFFRACTION4{A|3917 - 3946}A3917 - 3946
5X-RAY DIFFRACTION5{A|3954 - 3968}A3954 - 3968
6X-RAY DIFFRACTION6{B|3814 - 3828}B3814 - 3828
7X-RAY DIFFRACTION7{B|3829 - 3847}B3829 - 3847
8X-RAY DIFFRACTION8{B|3848 - 3913}B3848 - 3913
9X-RAY DIFFRACTION9{B|3914 - 3946}B3914 - 3946
10X-RAY DIFFRACTION10{B|3954 - 3968}B3954 - 3968

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