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- PDB-6s79: Crystal structure of CARM1 in complex with inhibitor AA183 -

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Basic information

Entry
Database: PDB / ID: 6s79
TitleCrystal structure of CARM1 in complex with inhibitor AA183
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-KXW / Histone-arginine methyltransferase CARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsGunnell, E.A. / Al-Noori, A. / 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)162,28410
Polymers160,0944
Non-polymers2,1906
Water4,810267
1
A: Histone-arginine methyltransferase CARM1
D: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,0504
Polymers80,0472
Non-polymers1,0032
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3510 Å2
ΔGint-25 kcal/mol
Surface area26320 Å2
MethodPISA
2
B: Histone-arginine methyltransferase CARM1
C: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,2346
Polymers80,0472
Non-polymers1,1874
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3840 Å2
ΔGint-28 kcal/mol
Surface area26320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.479, 99.196, 208.439
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11B-679-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 135 through 413 or resid 415...
21(chain B and (resid 135 through 413 or resid 415...
31(chain C and (resid 135 through 413 or resid 415...
41(chain D and (resid 135 through 413 or resid 415...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 135 through 413 or resid 415...A135 - 413
121(chain A and (resid 135 through 413 or resid 415...A415 - 464
131(chain A and (resid 135 through 413 or resid 415...A466 - 467
141(chain A and (resid 135 through 413 or resid 415...A469 - 475
211(chain B and (resid 135 through 413 or resid 415...B135 - 413
221(chain B and (resid 135 through 413 or resid 415...B415 - 464
231(chain B and (resid 135 through 413 or resid 415...B466 - 467
241(chain B and (resid 135 through 413 or resid 415...B469 - 475
311(chain C and (resid 135 through 413 or resid 415...C135 - 413
321(chain C and (resid 135 through 413 or resid 415...C415 - 464
331(chain C and (resid 135 through 413 or resid 415...C466 - 467
341(chain C and (resid 135 through 413 or resid 415...C469 - 475
411(chain D and (resid 135 through 413 or resid 415...D135 - 413
421(chain D and (resid 135 through 413 or resid 415...D415 - 464
431(chain D and (resid 135 through 413 or resid 415...D466 - 467
441(chain D and (resid 135 through 413 or resid 415...D469 - 475

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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-KXW / (2~{S})-4-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl-[3-(pyridin-2-ylamino)propyl]amino]-2-azanyl-butanoic acid


Mass: 501.539 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H31N9O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 267 / 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: 2.51 Å3/Da / Density % sol: 50.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.1 M Bis-tris propane, 0.2 M sodium formate, 20 % (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 8, 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: 2.1→104.23 Å / Num. obs: 92162 / % possible obs: 100 % / Redundancy: 6.6 % / Biso Wilson estimate: 37.03 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.186 / Rpim(I) all: 0.078 / Rrim(I) all: 0.202 / Net I/σ(I): 7.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.1-2.146.82.51644830.2871.042.72599.9
11.5-104.235.40.0566720.9970.0260.06299.5

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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: 2.1→71.852 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 25.23
RfactorNum. reflection% reflectionSelection details
Rfree0.2311 4544 4.94 %RANDOM
Rwork0.1988 ---
obs0.2004 92045 99.89 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 118.44 Å2 / Biso mean: 45.3979 Å2 / Biso min: 19.52 Å2
Refinement stepCycle: final / Resolution: 2.1→71.852 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10976 0 228 267 11471
Biso mean--51.13 42.83 -
Num. residues----1368
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A6523X-RAY DIFFRACTION11.59TORSIONAL
12B6523X-RAY DIFFRACTION11.59TORSIONAL
13C6523X-RAY DIFFRACTION11.59TORSIONAL
14D6523X-RAY DIFFRACTION11.59TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1-2.12390.34091270.330828933020100
2.1239-2.14890.33941440.326929123056100
2.1489-2.17510.34131510.323328412992100
2.1751-2.20260.33411540.317828623016100
2.2026-2.23160.3391460.298929083054100
2.2316-2.26220.29281510.299128903041100
2.2622-2.29450.30841640.28228603024100
2.2945-2.32870.32341470.28428673014100
2.3287-2.36510.30451600.274629023062100
2.3651-2.40390.28771390.268729043043100
2.4039-2.44530.32111440.265729053049100
2.4453-2.48980.29151630.253128553018100
2.4898-2.53770.31391350.244229303065100
2.5377-2.58950.27491510.239628823033100
2.5895-2.64580.28061720.237728553027100
2.6458-2.70740.27571560.233229123068100
2.7074-2.77510.29181570.219829023059100
2.7751-2.85010.23471570.215328823039100
2.8501-2.9340.29461740.209128913065100
2.934-3.02870.2691540.21729343088100
3.0287-3.13690.26991530.208429123065100
3.1369-3.26250.25051350.195529273062100
3.2625-3.4110.24471570.190229213078100
3.411-3.59080.20751420.179629423084100
3.5908-3.81580.18681440.162629573101100
3.8158-4.11040.18981470.153829493096100
4.1104-4.5240.17151450.144229823127100
4.524-5.17850.1591680.140729643132100
5.1785-6.52360.18341610.174430133174100
6.5236-71.89450.17721460.1683147329398
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)
11.2525-0.1841-0.28131.325-0.43751.67260.1565-0.11460.02560.0383-0.0058-0.0692-0.15750.1414-0.02370.6105-0.0880.01840.5817-0.05230.2932-19.570616.7507-9.1447
20.5747-0.43710.30690.6836-0.4770.56780.12530.10130.00080.0085-0.1083-0.01760.08040.0436-0.05490.5924-0.05530.05980.6412-0.04030.2769-24.921525.734-31.8875
31.0192-0.15860.3110.6593-1.06951.60770.0830.17720.0139-0.0198-0.114-0.0140.11080.17580.02530.5885-0.01580.03540.6118-0.04720.2778-16.044321.8826-35.8165
42.37780.2399-1.06461.0728-0.70153.20280.2518-0.07440.09710.2941-0.16330.1931-0.02030.1071-0.07190.5669-0.0070.02650.7034-0.04550.3781-24.126627.3984-40.1542
51.1388-0.20920.10421.04660.54831.66910.12450.06660.08830.06950.0328-0.0316-0.1175-0.0514-0.10390.27810.04070.04960.19780.04010.2364-55.303719.5426-93.0268
60.95770.4-0.0110.1740.2390.82270.2845-0.41570.050.2009-0.1185-0.0113-0.00020.0706-0.16170.39440.00090.0480.3569-0.00510.2452-44.015427.1566-65.3749
71.2312-0.16610.33081.02160.54632.08230.11-0.32590.08170.2232-0.0278-0.0577-0.0059-0.0343-0.08510.34570.00020.05140.32720.03430.2532-56.531524.1535-67.6464
82.97231.4482-0.09563.0825-0.7163.83570.04380.3740.2714-0.3589-0.14070.3546-0.117-0.21120.10520.47080.01820.02560.4187-0.08350.4467-30.910337.7609-85.4439
91.38430.18890.36361.49020.10971.1623-0.0049-0.3070.24390.1681-0.06380.15510.0109-0.09260.11530.4172-0.04280.02990.3507-0.09080.2674-18.868641.6481-68.9848
101.28140.98010.65252.06260.66551.0230.0222-0.13630.00220.10940.08780.13210.0419-0.01510.06980.3614-0.02280.01020.2863-0.04130.2169-17.493636.4211-82.6165
111.34250.67860.38810.40990.29390.51560.05020.0167-0.03460.0286-0.01880.08030.00040.02820.00120.25070.00420.00830.1745-0.0070.2221-27.897413.9396-89.3047
121.08640.75210.0491.83690.73481.1188-0.0427-0.0112-0.05160.10060.0368-0.20410.04440.0772-0.06390.2697-0.02010.02020.2524-0.00480.2136-12.179520.9488-84.0016
131.92940.69010.20151.87360.91331.7902-0.02230.3124-0.3038-0.5477-0.16830.01610.0838-0.0942-0.05730.42080.00130.03820.27060.00630.3073-16.18518.0812-92.6486
141.70940.0090.16982.5651-0.10050.7998-0.06580.09590.0198-0.03490.00860.066-0.03-0.0504-0.00080.2794-0.04190.02340.25950.00290.2071-20.847618.7896-94.2293
151.5765-0.04750.14541.3162-0.30941.2059-0.02640.03230.20450.2161-0.01430.0009-0.1611-0.07540.11550.66160.0560.02910.6045-0.00090.3144-51.713442.0478-32.0728
160.6656-0.15210.40270.4445-0.30610.66710.10620.0333-0.098-0.0082-0.07750.1436-0.0887-0.14980.01620.63970.02270.06390.5638-0.03950.2959-49.58222.1283-16.8141
170.7246-0.5562-0.16971.7146-0.35630.90150.0018-0.0372-0.07770.21050.01960.1828-0.1011-0.1057-0.08240.54910.0140.09070.5959-0.05520.3146-59.052920.4091-16.1113
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 456 )A336 - 456
4X-RAY DIFFRACTION4chain 'A' and (resid 457 through 476 )A457 - 476
5X-RAY DIFFRACTION5chain 'B' and (resid 135 through 278 )B135 - 278
6X-RAY DIFFRACTION6chain 'B' and (resid 279 through 335 )B279 - 335
7X-RAY DIFFRACTION7chain 'B' and (resid 336 through 476 )B336 - 476
8X-RAY DIFFRACTION8chain 'C' and (resid 135 through 154 )C135 - 154
9X-RAY DIFFRACTION9chain 'C' and (resid 155 through 252 )C155 - 252
10X-RAY DIFFRACTION10chain 'C' and (resid 253 through 278 )C253 - 278
11X-RAY DIFFRACTION11chain 'C' and (resid 279 through 335 )C279 - 335
12X-RAY DIFFRACTION12chain 'C' and (resid 336 through 416 )C336 - 416
13X-RAY DIFFRACTION13chain 'C' and (resid 417 through 432 )C417 - 432
14X-RAY DIFFRACTION14chain 'C' and (resid 433 through 476 )C433 - 476
15X-RAY DIFFRACTION15chain 'D' and (resid 135 through 252 )D135 - 252
16X-RAY DIFFRACTION16chain 'D' and (resid 253 through 335 )D253 - 335
17X-RAY DIFFRACTION17chain 'D' and (resid 336 through 476 )D336 - 476

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