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- PDB-6s74: Crystal structure of CARM1 in complex with inhibitor UM305 -

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Basic information

Entry
Database: PDB / ID: 6s74
TitleCrystal structure of CARM1 in complex with inhibitor UM305
ComponentsHistone-arginine methyltransferase CARM1
KeywordsTRANSFERASE / Inhibitor / Complex / Arginine methyltransferase
Function / homology
Function and homology information


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 / histone H3R8 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 / histone H3R8 methyltransferase activity / histone H3R26 methyltransferase activity / histone H4R3 methyltransferase activity / histone H3K37 methyltransferase activity / histone H4K12 methyltransferase activity / histone H3K56 methyltransferase activity / protein-arginine N-methyltransferase activity / positive regulation of epithelial cell apoptotic process / histone H2A Q104 methyltransferase activity / histone methyltransferase activity / positive regulation of transcription by RNA polymerase I / nuclear replication fork / positive regulation of fat cell differentiation / response to cAMP / : / Regulation of lipid metabolism by PPARalpha / BMAL1:CLOCK,NPAS2 activates circadian expression / Activation of gene expression by SREBF (SREBP) / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / : / : / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / beta-catenin binding / Transcriptional regulation of white adipocyte differentiation / RMTs methylate histone arginines / : / DNA-binding transcription factor binding / methylation / Estrogen-dependent gene expression / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / 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 / : / Arginine methyltransferase oligomerization subdomain / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / Distorted Sandwich ...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 / : / Arginine methyltransferase oligomerization subdomain / 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-KY8 / Histone-arginine methyltransferase CARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.1 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
Revision 1.2May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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-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)162,20411
Polymers160,0944
Non-polymers2,1107
Water9,962553
1
A: Histone-arginine methyltransferase CARM1
C: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,2407
Polymers80,0472
Non-polymers1,1935
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4230 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)80,9644
Polymers80,0472
Non-polymers9172
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3420 Å2
ΔGint-23 kcal/mol
Surface area26010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.393, 99.029, 207.952
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 177 or resid 179...
21(chain B and (resid 135 through 177 or resid 179...
31(chain C and (resid 135 through 177 or resid 179...
41(chain D and (resid 135 through 177 or resid 179...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 135 through 177 or resid 179...A135 - 177
121(chain A and (resid 135 through 177 or resid 179...A179 - 219
131(chain A and (resid 135 through 177 or resid 179...A221 - 256
141(chain A and (resid 135 through 177 or resid 179...A337 - 4
151(chain A and (resid 135 through 177 or resid 179...A428 - 446
161(chain A and (resid 135 through 177 or resid 179...A428 - 444
171(chain A and (resid 135 through 177 or resid 179...A446 - 476
211(chain B and (resid 135 through 177 or resid 179...B135 - 177
221(chain B and (resid 135 through 177 or resid 179...B179 - 219
231(chain B and (resid 135 through 177 or resid 179...B135 - 476
241(chain B and (resid 135 through 177 or resid 179...B258 - 284
251(chain B and (resid 135 through 177 or resid 179...B428 - 446
261(chain B and (resid 135 through 177 or resid 179...B428 - 444
271(chain B and (resid 135 through 177 or resid 179...B446 - 476
311(chain C and (resid 135 through 177 or resid 179...C135 - 177
321(chain C and (resid 135 through 177 or resid 179...C179 - 219
331(chain C and (resid 135 through 177 or resid 179...C221 - 256
341(chain C and (resid 135 through 177 or resid 179...C258 - 284
351(chain C and (resid 135 through 177 or resid 179...C286 - 335
361(chain C and (resid 135 through 177 or resid 179...C337 - 426
371(chain C and (resid 135 through 177 or resid 179...C428 - 444
381(chain C and (resid 135 through 177 or resid 179...C446 - 476
411(chain D and (resid 135 through 177 or resid 179...D135 - 177
421(chain D and (resid 135 through 177 or resid 179...D179 - 219
431(chain D and (resid 135 through 177 or resid 179...D135 - 476
441(chain D and (resid 135 through 177 or resid 179...D258 - 284
451(chain D and (resid 135 through 177 or resid 179...D428 - 446
461(chain D and (resid 135 through 177 or resid 179...D428 - 444
471(chain D and (resid 135 through 177 or resid 179...D446 - 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-KY8 / (2~{R},3~{R},4~{S},5~{R})-2-(6-aminopurin-9-yl)-5-[[3-azanylpropyl-[3-(pyrimidin-2-ylamino)propyl]amino]methyl]oxolane-3,4-diol


Mass: 458.517 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H30N10O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 553 / 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: 2.49 Å3/Da / Density % sol: 50.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1 M Bis-tris propane, 0.02 M sodium phosphate, 22 % (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: 2.1→48.17 Å / Num. obs: 80206 / % possible obs: 87.8 % / Redundancy: 3.8 % / Biso Wilson estimate: 33.05 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.034 / Rrim(I) all: 0.073 / Net I/σ(I): 11.6 / Num. measured all: 302969 / Scaling rejects: 55
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.1-2.143.60.4961683646440.8180.2690.5682.290.1
10.71-48.173.70.02524346520.9990.0140.02931.280.9

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Processing

Software
NameVersionClassification
Aimless0.5.26data scaling
PHENIXrefinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementResolution: 2.1→48.168 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 23.05
RfactorNum. reflection% reflection
Rfree0.2156 4026 5.03 %
Rwork0.1923 --
obs0.1935 80113 87.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 88.37 Å2 / Biso mean: 36.7206 Å2 / Biso min: 18.22 Å2
Refinement stepCycle: final / Resolution: 2.1→48.168 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10976 0 216 553 11745
Biso mean--36.68 39.36 -
Num. residues----1368
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A6389X-RAY DIFFRACTION9.459TORSIONAL
12B6389X-RAY DIFFRACTION9.459TORSIONAL
13C6389X-RAY DIFFRACTION9.459TORSIONAL
14D6389X-RAY DIFFRACTION9.459TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 29

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1-2.12470.29521230.29142684280790
2.1247-2.15060.29631350.27862678281389
2.1506-2.17780.32221530.28012616276990
2.1778-2.20650.26461300.26332640277088
2.2065-2.23670.2761340.24752628276288
2.2367-2.26870.25241310.23862606273788
2.2687-2.30250.23361410.23542704284590
2.3025-2.33850.26431370.23042644278190
2.3385-2.37690.30491560.23912672282890
2.3769-2.41780.25551440.22292663280790
2.4178-2.46180.2411480.23052645279390
2.4618-2.50920.24561460.22772671281789
2.5092-2.56040.27261240.22072643276789
2.5604-2.6160.27191240.21842684280889
2.616-2.67690.21991410.21612628276988
2.6769-2.74380.24041500.21362564271487
2.7438-2.8180.26361480.20932631277988
2.818-2.90090.24741240.20932656278088
2.9009-2.99450.25081490.20472628277788
2.9945-3.10160.23321370.1982629276687
3.1016-3.22570.23791270.20892604273187
3.2257-3.37250.25881310.19292602273386
3.3725-3.55020.1921510.17332554270585
3.5502-3.77260.19151320.16272607273985
3.7726-4.06370.17871450.16042580272586
4.0637-4.47240.15021340.14392575270984
4.4724-5.1190.16331370.14092525266283
5.119-6.44690.18091430.17312560270383
6.4469-48.18060.17851510.17852566271779
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)
11.82320.2871-0.03511.3620.24571.2599-0.02910.1627-0.2024-0.1801-0.03420.06070.0667-0.08690.11690.32090.05640.0040.209-0.03310.198516.13039.698470.6733
20.7473-0.153-0.23590.34260.18510.29290.03350.01690.0001-0.0362-0.0285-0.01570.08410.02770.04540.26350.0465-0.00830.19380.01010.208114.022624.338685.7613
30.7853-0.03480.15741.59350.38391.2442-0.0017-0.05530.0434-0.0282-0.0541-0.0532-0.09280.041-0.05640.23070.0458-0.01870.21940.02340.226322.469730.723587.9153
42.0738-0.00750.18411.0095-0.15361.28640.0066-0.0333-0.2797-0.04180.00320.01750.4042-0.09290.06010.5346-0.0364-0.03530.3823-0.00470.2838-13.8947.60432.2514
50.51140.1292-0.21260.0797-0.19080.36880.07540.06380.05770.0344-0.02770.10210.1794-0.15590.00420.445-0.0375-0.03140.3634-0.01930.2626-11.762127.4916.8027
60.85610.43950.1431.0933-0.5140.60640.0866-0.040.0646-0.0449-0.06720.14020.1064-0.2407-0.06120.352-0.0378-0.02780.419-0.03450.2811-23.911328.996519.0043
71.12380.02550.0731.2743-0.11620.5150.030.1761-0.0026-0.2019-0.107-0.0866-0.00590.0982-0.01660.4445-0.0425-0.05950.4533-0.03730.2917-16.02329.41169.9959
81.19250.37310.25561.18360.15172.05590.1833-0.0967-0.0456-0.0431-0.00030.0250.1955-0.1141-0.06250.264-0.0496-0.02810.21290.02890.2376-16.207232.887894.1386
90.2896-0.02540.1930.72620.53231.40350.14320.0113-0.10160.0401-0.0636-0.00120.3353-0.3407-0.0070.2987-0.0928-0.05770.30030.06290.2828-22.897925.480686.1171
101.4448-0.3561-0.22650.34060.30890.7920.17250.37450.1465-0.3954-0.10560.04860.14760.0848-0.16080.42230.0515-0.04810.3382-0.01440.2493.405419.017559.2551
110.8645-0.103-0.27730.63120.69411.91160.11230.1621-0.0549-0.0947-0.006-0.0650.0688-0.1661-0.04450.2849-0.0121-0.06070.28020.03490.2491-18.900525.771567.6798
121.1582-0.54160.41411.3493-0.40081.48490.14940.1433-0.0614-0.0758-0.0810.02230.25090.12140.01510.40640.0726-0.0230.3621-0.03180.239918.130432.8688.948
130.28960.28930.00110.2112-0.02290.32130.0798-0.09440.01880.0517-0.04910.02550.03160.0523-0.00670.39190.0592-0.01890.3814-0.00840.287512.731424.000631.5753
140.7143-0.0941-0.30890.6467-0.63461.16060.0504-0.11070.01210.0709-0.07080.0333-0.04490.12050.03360.37730.0082-0.01560.4279-0.01630.271822.048130.386435.7193
150.51010.1172-0.53060.5209-0.07011.48950.06870.0142-0.1042-0.0696-0.02470.16980.23870.00330.03920.41560.0405-0.0350.4147-0.00040.329516.615919.878537.386
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 135 through 239 )A135 - 239
2X-RAY DIFFRACTION2chain 'A' and (resid 240 through 335 )A240 - 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 336 )B253 - 336
6X-RAY DIFFRACTION6chain 'B' and (resid 337 through 432 )B337 - 432
7X-RAY DIFFRACTION7chain 'B' and (resid 433 through 476 )B433 - 476
8X-RAY DIFFRACTION8chain 'C' and (resid 135 through 239 )C135 - 239
9X-RAY DIFFRACTION9chain 'C' and (resid 240 through 299 )C240 - 299
10X-RAY DIFFRACTION10chain 'C' and (resid 300 through 336 )C300 - 336
11X-RAY DIFFRACTION11chain 'C' and (resid 337 through 476 )C337 - 476
12X-RAY DIFFRACTION12chain 'D' and (resid 135 through 252 )D135 - 252
13X-RAY DIFFRACTION13chain 'D' and (resid 253 through 336 )D253 - 336
14X-RAY DIFFRACTION14chain 'D' and (resid 337 through 432 )D337 - 432
15X-RAY DIFFRACTION15chain 'D' and (resid 433 through 476 )D433 - 476

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