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- PDB-6s70: Crystal structure of CARM1 in complex with inhibitor UM251 -

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Basic information

Entry
Database: PDB / ID: 6s70
TitleCrystal structure of CARM1 in complex with inhibitor UM251
ComponentsHistone-arginine methyltransferase CARM1
KeywordsTRANSFERASE / Inhibitor / Complex / Arginine methyltransferase
Function / homology
Function and homology information


: / histone H3R17 methyltransferase activity / histone H3R2 methyltransferase activity / negative regulation of dendrite development / type I protein arginine methyltransferase / protein-arginine omega-N asymmetric methyltransferase activity / protein methyltransferase activity / histone arginine N-methyltransferase activity / regulation of intracellular estrogen receptor signaling pathway / replication fork reversal ...: / histone H3R17 methyltransferase activity / histone H3R2 methyltransferase activity / negative regulation of dendrite development / type I protein arginine methyltransferase / protein-arginine omega-N asymmetric methyltransferase activity / protein methyltransferase activity / histone arginine N-methyltransferase activity / regulation of intracellular estrogen receptor signaling pathway / replication fork reversal / protein-arginine N-methyltransferase activity / positive regulation of epithelial cell apoptotic process / positive regulation of transcription by RNA polymerase I / histone methyltransferase activity / nuclear replication fork / positive regulation of fat cell differentiation / response to cAMP / RORA activates gene expression / Regulation of lipid metabolism by PPARalpha / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / BMAL1:CLOCK,NPAS2 activates circadian gene expression / nuclear receptor coactivator activity / Activation of gene expression by SREBF (SREBP) / lysine-acetylated histone binding / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / RMTs methylate histone arginines / beta-catenin binding / Transcriptional regulation of white adipocyte differentiation / Circadian Clock / DNA-binding transcription factor binding / Estrogen-dependent gene expression / transcription coactivator activity / transcription cis-regulatory region binding / positive regulation of cell population proliferation / regulation of DNA-templated transcription / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Histone-arginine methyltransferase CARM1, N-terminal / Coactivator-associated arginine methyltransferase 1 N terminal / Ribosomal protein L11 methyltransferase (PrmA) / Hnrnp arginine n-methyltransferase1 / Hnrnp arginine n-methyltransferase1 / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / Distorted Sandwich / PH-like domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-KYB / Histone-arginine methyltransferase CARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsGunnell, E.A. / Muhsen, U. / Dowden, J. / Dreveny, I.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)1501569 United Kingdom
CitationJournal: Biochem.J. / Year: 2020
Title: Structural and biochemical evaluation of bisubstrate inhibitors of protein arginine N-methyltransferases PRMT1 and CARM1 (PRMT4).
Authors: Gunnell, E.A. / Al-Noori, A. / Muhsen, U. / Davies, C.C. / Dowden, J. / Dreveny, I.
History
DepositionJul 4, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 11, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone-arginine methyltransferase CARM1
B: Histone-arginine methyltransferase CARM1
C: Histone-arginine methyltransferase CARM1
D: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)162,17211
Polymers160,0944
Non-polymers2,0787
Water6,756375
1
A: Histone-arginine methyltransferase CARM1
C: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,1326
Polymers80,0472
Non-polymers1,0854
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4130 Å2
ΔGint-23 kcal/mol
Surface area26450 Å2
MethodPISA
2
B: Histone-arginine methyltransferase CARM1
D: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,0405
Polymers80,0472
Non-polymers9933
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3820 Å2
ΔGint-22 kcal/mol
Surface area26600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.684, 98.677, 207.100
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 135 through 160 or resid 162...
21(chain B and (resid 135 through 160 or resid 162...
31(chain C and (resid 135 through 160 or resid 162...
41(chain D and (resid 135 through 160 or resid 162...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 135 through 160 or resid 162...A135 - 160
121(chain A and (resid 135 through 160 or resid 162...A162 - 167
131(chain A and (resid 135 through 160 or resid 162...A135 - 476
141(chain A and (resid 135 through 160 or resid 162...A428 - 43
151(chain A and (resid 135 through 160 or resid 162...A428 - 437
161(chain A and (resid 135 through 160 or resid 162...A439 - 476
211(chain B and (resid 135 through 160 or resid 162...B135 - 160
221(chain B and (resid 135 through 160 or resid 162...B162 - 167
231(chain B and (resid 135 through 160 or resid 162...B135 - 476
241(chain B and (resid 135 through 160 or resid 162...B378 - 413
251(chain B and (resid 135 through 160 or resid 162...B415 - 426
261(chain B and (resid 135 through 160 or resid 162...B428 - 437
271(chain B and (resid 135 through 160 or resid 162...B439 - 476
311(chain C and (resid 135 through 160 or resid 162...C135 - 160
321(chain C and (resid 135 through 160 or resid 162...C162 - 167
331(chain C and (resid 135 through 160 or resid 162...C169 - 376
341(chain C and (resid 135 through 160 or resid 162...C378 - 413
351(chain C and (resid 135 through 160 or resid 162...C415 - 426
361(chain C and (resid 135 through 160 or resid 162...C428 - 437
371(chain C and (resid 135 through 160 or resid 162...C439 - 476
411(chain D and (resid 135 through 160 or resid 162...D135 - 160
421(chain D and (resid 135 through 160 or resid 162...D162 - 167
431(chain D and (resid 135 through 160 or resid 162...D169 - 376
441(chain D and (resid 135 through 160 or resid 162...D428 - 43
451(chain D and (resid 135 through 160 or resid 162...D428 - 437
461(chain D and (resid 135 through 160 or resid 162...D439 - 476

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Components

#1: Protein
Histone-arginine methyltransferase CARM1 / Coactivator-associated arginine methyltransferase 1 / Protein arginine N-methyltransferase 4


Mass: 40023.484 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CARM1, PRMT4 / Production host: Escherichia coli (E. coli)
References: UniProt: Q86X55, type I protein arginine methyltransferase
#2: Chemical
ChemComp-KYB / 1-[5-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl-(3-azanylpropyl)amino]pentyl]guanidine


Mass: 450.538 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H34N10O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 375 / 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: 2.45 Å3/Da / Density % sol: 49.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1 M Bis-tris propane, 0.2 M sodium acetate, 24 % (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 27, 2016
RadiationMonochromator: Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.3→57.23 Å / Num. obs: 66028 / % possible obs: 96.2 % / Redundancy: 4.2 % / Biso Wilson estimate: 38.97 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.034 / Rrim(I) all: 0.074 / Net I/σ(I): 13.8 / Num. measured all: 276271 / Scaling rejects: 38
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.3-2.3540.54643610.7650.2950.62595.8
6.5378-57.233.80.0227050.9990.0120.02590

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Processing

Software
NameVersionClassification
PHENIXrefinement
Aimless0.5.32data scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→57.23 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 21.94
RfactorNum. reflection% reflection
Rfree0.2115 3257 4.94 %
Rwork0.1848 --
obs0.1862 65968 95.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 106 Å2 / Biso mean: 41.9496 Å2 / Biso min: 17.28 Å2
Refinement stepCycle: final / Resolution: 2.3→57.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10976 0 146 375 11497
Biso mean--52.48 41.72 -
Num. residues----1368
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A6411X-RAY DIFFRACTION11.913TORSIONAL
12B6411X-RAY DIFFRACTION11.913TORSIONAL
13C6411X-RAY DIFFRACTION11.913TORSIONAL
14D6411X-RAY DIFFRACTION11.913TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 23

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3-2.33430.27561340.26152669280395
2.3343-2.37080.29761300.25542666279696
2.3708-2.40970.29571450.25472626277193
2.4097-2.45120.28391470.2382726287399
2.4512-2.49580.28481500.23542756290698
2.4958-2.54380.26351380.23242777291599
2.5438-2.59570.27141570.23012751290898
2.5957-2.65220.25291620.21912739290198
2.6522-2.71390.25771320.21372723285597
2.7139-2.78170.27451240.21252754287897
2.7817-2.85690.22581170.19982770288797
2.8569-2.9410.24061430.20352617276092
2.941-3.03590.21621410.18522717285897
3.0359-3.14440.2471410.18522780292197
3.1444-3.27030.23531370.19012747288497
3.2703-3.41910.23871480.19112748289697
3.4191-3.59940.20421550.17972727288296
3.5994-3.82480.19111320.16352666279893
3.8248-4.12010.191380.16442722286095
4.1201-4.53460.17391560.1522758291496
4.5346-5.19030.17311310.14672779291095
5.1903-6.53780.18971500.17852677282792
6.5378-57.24940.161490.1752816296591
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)
11.56440.58280.16561.8176-0.00091.5848-0.00830.1693-0.2024-0.07380.01550.09080.1242-0.01710.05960.34640.061-0.03160.3121-0.08530.28516.68868.165671.5841
20.6805-0.3829-0.0750.470.16060.48830.04640.06340.0595-0.0149-0.0083-0.02040.05420.07950.01080.19850.012-0.01550.201-0.01260.230713.192228.118486.5796
30.8311-0.37440.01491.88720.26131.5094-0.01590.02630.0270.0261-0.0152-0.0767-0.04290.0973-0.05820.16770.0258-0.03640.2537-0.01130.228522.46830.836487.4276
42.0343-0.11140.30181.8128-0.47021.57410.0064-0.1093-0.1284-0.10440.03840.04110.0944-0.02410.06220.4967-0.0593-0.01430.41640.02690.3112-13.89767.003831.8496
50.46520.5177-0.12940.6708-0.32550.2610.1138-0.05080.06310.0915-0.07260.09740.0022-0.0793-0.00220.4474-0.049-0.01620.3568-0.01030.3443-11.715427.127416.759
60.76890.43580.14461.8139-0.81740.74610.0133-0.00960.1059-0.16140.00980.2343-0.0157-0.0454-0.10370.4508-0.054-0.0610.4034-0.04670.3382-21.100128.869416.3259
71.59170.10270.64291.11240.13632.22940.0941-0.0558-0.186-0.11570.0469-0.02040.22860.0115-0.03690.2516-0.0463-0.04760.21890.02160.2728-16.554331.154794.2299
80.8486-0.26890.23770.55610.52272.13580.1278-0.0624-0.1507-0.0437-0.0808-0.12010.37430.04450.03810.3104-0.065-0.06210.26230.03290.3284-22.489325.710481.9743
91.4038-0.7089-0.4320.58210.27770.59370.33840.47640.1241-0.4663-0.17790.09530.03660.1555-0.24160.43280.0488-0.07920.5134-0.03250.32684.52418.40558.0089
101.3031-0.4222-0.23971.03470.96131.90180.13930.2717-0.088-0.1762-0.0816-0.02630.0658-0.0082-0.00620.30910.003-0.08880.32230.02090.2772-20.264428.159567.338
110.98270.0205-0.94120.85820.23991.09280.1620.1556-0.11920.0258-0.1099-0.15930.24950.2628-0.04650.36590.0304-0.07190.37030.00570.3501-14.29518.160565.8962
121.17-0.43770.47511.217-0.13611.42540.06450.0028-0.02510.0054-0.012-0.10130.14760.06610.00340.49860.0037-0.00230.3676-0.01750.290517.886732.6379.2446
130.77310.4407-0.05360.3121-0.22190.17420.0982-0.23090.07630.1011-0.0630.0082-0.0701-0.0787-0.04660.5020.0004-0.02510.4229-0.03460.304412.430123.246331.9489
140.8664-0.0203-0.57770.6817-0.8361.39810.055-0.18970.06660.0373-0.09130.0339-0.20640.05120.01970.5113-0.0397-0.07180.4482-0.04880.320421.658629.710136.1605
150.96490.2191-0.14510.27250.14731.82440.0398-0.2422-0.0093-0.1786-0.08570.05260.161-0.1932-0.01160.5487-0.0623-0.08570.481-0.02340.365716.604719.40837.6063
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 135 through 252 )A135 - 252
2X-RAY DIFFRACTION2chain 'A' and (resid 253 through 335 )A253 - 335
3X-RAY DIFFRACTION3chain 'A' and (resid 336 through 476 )A336 - 476
4X-RAY DIFFRACTION4chain 'B' and (resid 135 through 252 )B135 - 252
5X-RAY DIFFRACTION5chain 'B' and (resid 253 through 335 )B253 - 335
6X-RAY DIFFRACTION6chain 'B' and (resid 336 through 476 )B336 - 476
7X-RAY DIFFRACTION7chain 'C' and (resid 135 through 252 )C135 - 252
8X-RAY DIFFRACTION8chain 'C' and (resid 253 through 299 )C253 - 299
9X-RAY DIFFRACTION9chain 'C' and (resid 300 through 335 )C300 - 335
10X-RAY DIFFRACTION10chain 'C' and (resid 336 through 432 )C336 - 432
11X-RAY DIFFRACTION11chain 'C' and (resid 433 through 476 )C433 - 476
12X-RAY DIFFRACTION12chain 'D' and (resid 135 through 252 )D135 - 252
13X-RAY DIFFRACTION13chain 'D' and (resid 253 through 335 )D253 - 335
14X-RAY DIFFRACTION14chain 'D' and (resid 336 through 432 )D336 - 432
15X-RAY DIFFRACTION15chain 'D' and (resid 433 through 476 )D433 - 476

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