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- PDB-6s7b: Crystal structure of CARM1 in complex with inhibitor UM249 -

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Basic information

Entry
Database: PDB / ID: 6s7b
TitleCrystal structure of CARM1 in complex with inhibitor UM249
ComponentsHistone-arginine methyltransferase CARM1
KeywordsTRANSFERASE / Inhibitor / Complex / Arginine methyltransferase
Function / homology
Function and homology information


histone H3R17 methyltransferase activity / histone H3R2 methyltransferase activity / type I protein arginine methyltransferase / negative regulation of dendrite development / protein-arginine omega-N asymmetric methyltransferase activity / histone arginine N-methyltransferase activity / protein methyltransferase activity / regulation of intracellular estrogen receptor signaling pathway / replication fork reversal / protein-arginine N-methyltransferase activity ...histone H3R17 methyltransferase activity / histone H3R2 methyltransferase activity / type I protein arginine methyltransferase / negative regulation of dendrite development / protein-arginine omega-N asymmetric methyltransferase activity / histone arginine N-methyltransferase activity / protein 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 / Activation of gene expression by SREBF (SREBP) / nuclear receptor coactivator activity / lysine-acetylated histone binding / Heme signaling / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / beta-catenin binding / RMTs methylate histone arginines / Transcriptional regulation of white adipocyte differentiation / Circadian Clock / DNA-binding transcription factor binding / Estrogen-dependent gene expression / methylation / 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 / PH-like domain superfamily ...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-KYH / Histone-arginine methyltransferase CARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.659 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 1.2Jan 24, 2024Group: 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)161,8408
Polymers160,0944
Non-polymers1,7464
Water2,018112
1
A: Histone-arginine methyltransferase CARM1
C: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,9204
Polymers80,0472
Non-polymers8732
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3610 Å2
ΔGint-22 kcal/mol
Surface area26050 Å2
MethodPISA
2
B: Histone-arginine methyltransferase CARM1
D: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,9204
Polymers80,0472
Non-polymers8732
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3540 Å2
ΔGint-24 kcal/mol
Surface area26220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.455, 99.367, 208.463
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:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11SERSERGLNGLN(chain A and (resid 135 through 160 or resid 162...AA135 - 1601 - 26
12METMETTHRTHR(chain A and (resid 135 through 160 or resid 162...AA162 - 41328 - 279
13TRPTRPPHEPHE(chain A and (resid 135 through 160 or resid 162...AA415 - 473281 - 339
14ARGARGTYRTYR(chain A and (resid 135 through 160 or resid 162...AA475 - 476341 - 342
21SERSERGLNGLN(chain B and (resid 135 through 160 or resid 162...BB135 - 1601 - 26
22METMETTHRTHR(chain B and (resid 135 through 160 or resid 162...BB162 - 41328 - 279
23TRPTRPPHEPHE(chain B and (resid 135 through 160 or resid 162...BB415 - 473281 - 339
24ARGARGTYRTYR(chain B and (resid 135 through 160 or resid 162...BB475 - 476341 - 342
31SERSERGLNGLN(chain C and (resid 135 through 160 or resid 162...CC135 - 1601 - 26
32METMETTHRTHR(chain C and (resid 135 through 160 or resid 162...CC162 - 41328 - 279
33TRPTRPPHEPHE(chain C and (resid 135 through 160 or resid 162...CC415 - 473281 - 339
34ARGARGTYRTYR(chain C and (resid 135 through 160 or resid 162...CC475 - 476341 - 342
41SERSERGLNGLN(chain D and (resid 135 through 160 or resid 162...DD135 - 1601 - 26
42METMETTHRTHR(chain D and (resid 135 through 160 or resid 162...DD162 - 41328 - 279
43TRPTRPPHEPHE(chain D and (resid 135 through 160 or resid 162...DD415 - 473281 - 339
44ARGARGTYRTYR(chain D and (resid 135 through 160 or resid 162...DD475 - 476341 - 342

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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-KYH / 1-[4-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl-(3-azanylpropyl)amino]butyl]guanidine


Mass: 436.512 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H32N10O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 112 / 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: 49.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1 M Bis-tris propane, 0.02 M potassium phosphate, 22 % (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Feb 4, 2016
RadiationMonochromator: Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.659→57.74 Å / Num. obs: 45903 / % possible obs: 99.9 % / Redundancy: 6.4 % / Biso Wilson estimate: 44.22 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.21 / Rpim(I) all: 0.09 / Rrim(I) all: 0.229 / Net I/σ(I): 10.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.659-2.6686.41.0524370.7810.451.14698
12.343-57.745.50.0585360.9990.0270.06498.3

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Processing

Software
NameVersionClassification
PHENIXrefinement
Aimlessdata scaling
PDB_EXTRACT3.24data extraction
XDSdata scaling
PHASERphasing
REFMACrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2Y1X

2y1x


Resolution: 2.659→57.74 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 23.83
RfactorNum. reflection% reflectionSelection details
Rfree0.2267 2236 4.88 %RANDOM
Rwork0.1939 ---
obs0.1955 45808 99.69 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 103.3 Å2 / Biso mean: 42.7935 Å2 / Biso min: 15.53 Å2
Refinement stepCycle: final / Resolution: 2.659→57.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10976 0 124 112 11212
Biso mean--62.01 35.68 -
Num. residues----1368
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A6546X-RAY DIFFRACTION13.543TORSIONAL
12B6546X-RAY DIFFRACTION13.543TORSIONAL
13C6546X-RAY DIFFRACTION13.543TORSIONAL
14D6546X-RAY DIFFRACTION13.543TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.6593-2.71710.3341470.2972668100
2.7171-2.78030.30081490.27662672100
2.7803-2.84990.29351380.29272662100
2.8499-2.92690.26471230.25352718100
2.9269-3.0130.26591410.23312697100
3.013-3.11030.2591340.22212697100
3.1103-3.22150.2481320.21752692100
3.2215-3.35040.27151400.21072702100
3.3504-3.50290.23971280.19362705100
3.5029-3.68760.22211380.18262746100
3.6876-3.91850.20761390.18092720100
3.9185-4.2210.19921420.1682716100
4.221-4.64570.20611440.16062747100
4.6457-5.31760.18961410.1522749100
5.3176-6.69830.21121550.18482785100
6.6983-57.740.18931450.1773289698
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)
12.11470.188-0.07051.80160.86922.3316-0.0750.0316-0.2719-0.0428-0.03920.180.0984-0.21050.20430.33960.04940.02180.25-0.01990.3075-20.62459.4833-30.4679
22.091-0.9238-0.83230.57480.42650.75610.1141-0.06250.011-0.1285-0.05350.0437-0.06490.087-0.03210.18440.02190.01440.10190.01140.1613-27.968535.693-14.8417
31.2547-0.61-0.18262.49441.18562.1006-0.0281-0.02510.0111-0.03380.0054-0.3235-0.18670.1724-0.1430.17640.0351-0.01010.18360.01220.2426-13.037830.5901-18.9982
41.7097-0.1898-0.30662.70190.21792.01380.06-0.11840.08530.0711-0.0197-0.00110.0073-0.0264-0.01850.22040.0689-0.03770.22370.00670.2637-20.872130.7961-10.4969
52.601-0.3140.33262.07840.07012.7280.0597-0.045-0.2871-0.1367-0.0813-0.1230.43290.09860.16650.4525-0.0471-0.010.35590.05020.289-51.55817.7421-71.7598
60.8730.2267-0.3880.4075-0.20930.63790.0745-0.0467-0.04170.0507-0.07280.00210.1159-0.09330.03140.2721-0.0183-0.03080.2785-0.03320.1649-49.538227.5466-87.2943
71.47090.6482-0.4682.5641-1.00371.6528-0.008-0.02370.0219-0.16230.00120.15330.0899-0.1721-0.06930.2307-0.0194-0.04510.3238-0.06050.2553-59.063329.2918-88.0075
82.32530.4699-0.31020.75620.26312.30290.1957-0.0512-0.2598-0.0520.07020.01220.32690.086-0.11070.337-0.0277-0.07030.270.02190.3049-53.531831.3645-14.1393
92.53210.08250.48951.41190.46533.12890.2202-0.2112-0.25110.2172-0.12240.02090.2908-0.1065-0.07830.3105-0.0653-0.00830.26080.06720.281-55.896932.218-3.2856
100.2504-0.2928-0.64660.6380.80523.27650.1845-0.1033-0.0641-0.0374-0.073-0.0030.40630.03440.05460.3219-0.0916-0.07470.27540.04270.3028-60.672826.339-21.3655
111.7027-1.3446-0.66420.93420.66251.12520.03790.2222-0.0867-0.4638-0.02760.06490.23480.1965-0.22520.48920.0476-0.05780.3747-0.02180.3147-33.736919.3179-45.4466
123.0246-0.1619-0.8511.07851.30022.86190.24210.1841-0.1826-0.0933-0.20250.0539-0.0359-0.3810.0050.30720.0358-0.10950.31640.04630.3267-58.727826.6001-32.9982
131.5656-0.202-1.04070.69391.06913.41130.15640.1854-0.04-0.12-0.0374-0.0614-0.0709-0.2018-0.01740.30490.0013-0.06830.29180.06710.2481-57.545826.5241-36.9759
141.7890.9928-0.60751.78090.90783.15990.32120.0098-0.42270.1712-0.108-0.20360.1064-0.0202-0.08690.41970.0831-0.06450.37590.03170.408-49.300121.4793-40.0093
151.5278-0.592-0.62020.8525-0.75151.38910.0777-0.0758-0.22930.10320.03330.12070.1678-0.14-0.06260.3234-0.0048-0.09430.37060.03150.2827-24.443630.7912-88.142
161.5885-0.7490.50021.57120.01181.67440.00630.16070.0073-0.114-0.0144-0.02440.10080.047-0.00620.28760.0502-0.00190.3458-0.03780.2103-16.342934.4858-100.024
170.32150.0232-0.65120.4259-0.7322.46560.05760.0189-0.05270.0999-0.0073-0.0005-0.0331-0.22350.05450.30840.0027-0.01920.3333-0.02420.2897-13.279728.0369-82.9634
181.75411.2469-0.91791.1582-0.85431.16640.2445-0.32760.15980.2751-0.2175-0.15170.04070.0105-0.09520.40680.0356-0.00780.4836-0.01150.3157-39.723719.1195-58.8922
192.23220.5599-0.72111.1122-0.90021.73520.0486-0.1087-0.02180.1496-0.1157-0.0257-0.17270.12470.04050.3381-0.0061-0.0620.442-0.010.308-15.327228.152-71.3108
201.80570.4087-1.30260.8192-1.18432.09940.107-0.31140.05320.2216-0.09210.1134-0.31320.28070.00480.3615-0.0196-0.0290.3992-0.03730.2765-16.042231.5156-66.797
211.18870.1507-1.2971.37760.15142.37130.021-0.0615-0.10880.0331-0.11270.23840.1371-0.01040.08660.3432-0.0354-0.01130.4108-0.01790.2891-21.112920.1124-66.6952
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 135 through 278 )A135 - 278
2X-RAY DIFFRACTION2chain 'A' and (resid 279 through 335 )A279 - 335
3X-RAY DIFFRACTION3chain 'A' and (resid 336 through 432 )A336 - 432
4X-RAY DIFFRACTION4chain 'A' and (resid 433 through 476 )A433 - 476
5X-RAY DIFFRACTION5chain 'B' and (resid 135 through 252 )B135 - 252
6X-RAY DIFFRACTION6chain 'B' and (resid 253 through 335 )B253 - 335
7X-RAY DIFFRACTION7chain 'B' and (resid 336 through 476 )B336 - 476
8X-RAY DIFFRACTION8chain 'C' and (resid 135 through 196 )C135 - 196
9X-RAY DIFFRACTION9chain 'C' and (resid 197 through 252 )C197 - 252
10X-RAY DIFFRACTION10chain 'C' and (resid 253 through 299 )C253 - 299
11X-RAY DIFFRACTION11chain 'C' and (resid 300 through 335 )C300 - 335
12X-RAY DIFFRACTION12chain 'C' and (resid 336 through 368 )C336 - 368
13X-RAY DIFFRACTION13chain 'C' and (resid 369 through 456 )C369 - 456
14X-RAY DIFFRACTION14chain 'C' and (resid 457 through 476 )C457 - 476
15X-RAY DIFFRACTION15chain 'D' and (resid 135 through 178 )D135 - 178
16X-RAY DIFFRACTION16chain 'D' and (resid 179 through 252 )D179 - 252
17X-RAY DIFFRACTION17chain 'D' and (resid 253 through 299 )D253 - 299
18X-RAY DIFFRACTION18chain 'D' and (resid 300 through 335 )D300 - 335
19X-RAY DIFFRACTION19chain 'D' and (resid 336 through 368 )D336 - 368
20X-RAY DIFFRACTION20chain 'D' and (resid 369 through 432 )D369 - 432
21X-RAY DIFFRACTION21chain 'D' and (resid 433 through 476 )D433 - 476

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