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- PDB-6s71: Crystal structure of CARM1 in complex with inhibitor WH5C -

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Basic information

Entry
Database: PDB / ID: 6s71
TitleCrystal structure of CARM1 in complex with inhibitor WH5C
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-KYE / Histone-arginine methyltransferase CARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.062 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

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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)162,71715
Polymers160,0944
Non-polymers2,62311
Water9,620534
1
A: Histone-arginine methyltransferase CARM1
C: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,3127
Polymers80,0472
Non-polymers1,2655
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4130 Å2
ΔGint-27 kcal/mol
Surface area26060 Å2
MethodPISA
2
B: Histone-arginine methyltransferase CARM1
D: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,4048
Polymers80,0472
Non-polymers1,3576
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4480 Å2
ΔGint-28 kcal/mol
Surface area25850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.720, 98.630, 206.360
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 173 or resid 175...
21(chain B and (resid 135 through 173 or resid 175...
31(chain C and (resid 135 through 173 or resid 175...
41(chain D and (resid 135 through 173 or resid 175...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 135 through 173 or resid 175...A135 - 173
121(chain A and (resid 135 through 173 or resid 175...A175 - 207
131(chain A and (resid 135 through 173 or resid 175...A209 - 267
141(chain A and (resid 135 through 173 or resid 175...A269 - 348
151(chain A and (resid 135 through 173 or resid 175...A415 - 433
161(chain A and (resid 135 through 173 or resid 175...A415 - 437
171(chain A and (resid 135 through 173 or resid 175...A439 - 476
211(chain B and (resid 135 through 173 or resid 175...B135 - 173
221(chain B and (resid 135 through 173 or resid 175...B175 - 207
231(chain B and (resid 135 through 173 or resid 175...B209 - 267
241(chain B and (resid 135 through 173 or resid 175...B269 - 348
251(chain B and (resid 135 through 173 or resid 175...B415 - 433
261(chain B and (resid 135 through 173 or resid 175...B415 - 437
271(chain B and (resid 135 through 173 or resid 175...B439 - 476
311(chain C and (resid 135 through 173 or resid 175...C135 - 173
321(chain C and (resid 135 through 173 or resid 175...C175 - 207
331(chain C and (resid 135 through 173 or resid 175...C209 - 267
341(chain C and (resid 135 through 173 or resid 175...C269 - 348
351(chain C and (resid 135 through 173 or resid 175...C415 - 433
361(chain C and (resid 135 through 173 or resid 175...C415 - 437
371(chain C and (resid 135 through 173 or resid 175...C439 - 476
411(chain D and (resid 135 through 173 or resid 175...D135 - 173
421(chain D and (resid 135 through 173 or resid 175...D175 - 207
431(chain D and (resid 135 through 173 or resid 175...D209 - 267
441(chain D and (resid 135 through 173 or resid 175...D269 - 348
451(chain D and (resid 135 through 173 or resid 175...D415 - 433
461(chain D and (resid 135 through 173 or resid 175...D415 - 437
471(chain D and (resid 135 through 173 or resid 175...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-KYE / (2~{S})-4-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl-(5-carbamimidamidopentyl)amino]-2-azanyl-butanoic acid


Mass: 494.548 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H34N10O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 534 / 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: 2.44 Å3/Da / Density % sol: 49.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1 M Bis-tris propane, 0.2 M sodium acetate, 20 % (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 12, 2017
RadiationMonochromator: Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.062→103.18 Å / Num. obs: 91634 / % possible obs: 96.7 % / Redundancy: 3.7 % / Biso Wilson estimate: 37.76 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.033 / Rrim(I) all: 0.067 / Net I/σ(I): 11.8 / Num. measured all: 342936
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.4 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.062-2.0970.5381524345010.780.3250.6342.196.5
5.596-103.180.0381565446050.9980.0220.04426.990.8

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.062→103.18 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.73
RfactorNum. reflection% reflection
Rfree0.2099 1999 2.18 %
Rwork0.1857 --
obs0.1862 91570 96.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 123.13 Å2 / Biso mean: 44.5792 Å2 / Biso min: 21.53 Å2
Refinement stepCycle: final / Resolution: 2.062→103.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10976 0 182 534 11692
Biso mean--59.28 47.77 -
Num. residues----1368
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A6366X-RAY DIFFRACTION11.167TORSIONAL
12B6366X-RAY DIFFRACTION11.167TORSIONAL
13C6366X-RAY DIFFRACTION11.167TORSIONAL
14D6366X-RAY DIFFRACTION11.167TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0618-2.11330.29841390.27576259639897
2.1133-2.17050.3071440.25276393653798
2.1705-2.23440.24721420.23076375651797
2.2344-2.30650.25151430.21996412655598
2.3065-2.38890.25211420.20896404654697
2.3889-2.48460.22521440.20546417656197
2.4846-2.59770.21751440.19736415655998
2.5977-2.73460.22521420.1896376651897
2.7346-2.9060.22921430.19766428657197
2.906-3.13040.22311440.19126434657897
3.1304-3.44540.20011430.18436461660497
3.4454-3.9440.21491420.17066359650195
3.944-4.9690.17551440.15066431657595
4.969-103.30940.17551430.18336407655091
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)
11.3147-0.52920.88291.0863-0.30250.99720.0391-0.0788-0.0676-0.06190.0844-0.03020.14830.0594-00.514-0.04760.00060.44950.02870.3886-13.88817.0121-71.4543
20.78970.3846-0.1870.1242-0.1190.04550.0388-0.01370.0938-0.0449-0.02090.07110.0519-0.002900.4231-0.033-0.02470.3245-0.00620.3321-11.766827.0339-86.4517
30.58940.2610.41491.0643-0.3240.6263-0.0021-0.06210.0896-0.1565-0.00670.2001-0.00520.020800.4028-0.0346-0.04390.3527-0.02750.3815-21.213129.0391-87.0925
41.26140.68670.4661.3451-0.07331.13280.05730.1135-0.1519-0.0424-0.02990.15790.0822-0.0775-00.33160.0267-0.02650.3632-0.0680.350416.76958.3788-31.8304
50.2465-0.21640.0485-0.23470.00690.17560.04740.03680.0485-0.0352-0.0090.05090.01970.041300.22720.009-0.00560.2462-0.01710.325913.270128.1884-16.8731
60.4399-0.19920.27941.54330.05411.0727-0.00690.0220.00050.088-0.0041-0.0285-0.05410.0173-00.18910.0052-0.02310.2704-0.00240.284522.678130.8812-16.053
71.3152-0.5610.37960.99220.04210.95120.02580.0956-0.01050.030.063-0.09250.06460.0717-00.43930.00380.00890.336-0.010.316718.187632.8408-94.0782
80.41780.1170.38310.05030.02340.33120.0122-0.0092-0.0487-0.0026-0.0499-0.00560.0439-0.2497-00.5274-0.0087-0.00250.3827-0.00370.393424.056727.5905-81.8634
90.09610.1124-0.0330.19320.00930.0160.2172-0.45790.27940.2423-0.0569-0.0377-0.03410.070500.5074-0.0097-0.01860.5945-0.07080.4048-2.176718.165-58.0443
100.53730.13-0.16410.3212-0.45860.98710.1044-0.14980.056-0.0688-0.1044-0.0328-0.09710.001700.4627-0.0304-0.05020.4639-0.04230.334221.203627.5572-67.5463
110.2769-0.1753-0.23540.09580.01050.22940.29320.1331-0.2665-0.2736-0.32070.30050.2520.188-00.4843-0.0065-0.11490.6769-0.03960.477113.220421.7417-63.2559
121.00820.29570.52050.59950.11021.39350.0861-0.0493-0.1274-0.07250.0168-0.03550.17410.0253-00.2509-0.0307-0.03670.23250.02460.3104-17.230429.7206-10.9625
130.6636-0.31740.3670.0996-0.2290.13810.33130.29280.1254-0.1656-0.16870.0034-0.05350.05860.01090.3146-0.0033-0.05770.3386-0.01360.3186-5.787822.0359-38.7556
140.99410.016-0.17860.38820.55060.89350.09850.1454-0.0538-0.0195-0.0268-0.0013-0.00930.086700.30840.0152-0.05850.33440.00990.3166-19.594625.8438-35.8117
150.40360.1539-0.47490.27540.0410.49610.1810.0548-0.02780.0468-0.0729-0.26160.07030.1839-00.51830.1105-0.08680.6103-0.03210.4978-11.055520.8448-39.9801
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 456 )C336 - 456
11X-RAY DIFFRACTION11chain 'C' and (resid 457 through 476 )C457 - 476
12X-RAY DIFFRACTION12chain 'D' and (resid 135 through 278 )D135 - 278
13X-RAY DIFFRACTION13chain 'D' and (resid 279 through 335 )D279 - 335
14X-RAY DIFFRACTION14chain 'D' and (resid 336 through 456 )D336 - 456
15X-RAY DIFFRACTION15chain 'D' and (resid 457 through 476 )D457 - 476

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