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- PDB-6s7a: Crystal structure of CARM1 in complex with inhibitor AA175 -

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Basic information

Entry
Database: PDB / ID: 6s7a
TitleCrystal structure of CARM1 in complex with inhibitor AA175
ComponentsHistone-arginine methyltransferase CARM1
KeywordsTRANSFERASE / Inhibitor / Complex / Arginine methyltransferase
Function / homology
Function and homology information


histone H3R17 methyltransferase activity / negative regulation of dendrite development / histone H3R2 methyltransferase activity / protein-arginine omega-N asymmetric methyltransferase activity / type I protein arginine methyltransferase / : / protein methyltransferase activity / regulation of intracellular estrogen receptor signaling pathway / replication fork reversal / protein-arginine N-methyltransferase activity ...histone H3R17 methyltransferase activity / negative regulation of dendrite development / histone H3R2 methyltransferase activity / protein-arginine omega-N asymmetric methyltransferase activity / type I protein arginine methyltransferase / : / 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 / histone methyltransferase activity / positive regulation of transcription by RNA polymerase I / nuclear replication fork / response to cAMP / positive regulation of fat cell differentiation / : / 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 / : / methylation / DNA-binding transcription factor binding / 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 / cytoplasm / cytosol
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-KY5 / Histone-arginine methyltransferase CARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.86 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
Revision 1.2May 15, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)162,47714
Polymers160,0944
Non-polymers2,38310
Water12,394688
1
A: Histone-arginine methyltransferase CARM1
C: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,1466
Polymers80,0472
Non-polymers1,0994
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4040 Å2
ΔGint-26 kcal/mol
Surface area26070 Å2
MethodPISA
2
B: Histone-arginine methyltransferase CARM1
D: Histone-arginine methyltransferase CARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,3308
Polymers80,0472
Non-polymers1,2836
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4570 Å2
ΔGint-29 kcal/mol
Surface area25830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.784, 98.624, 207.137
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-777-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 135 through 303 or resid 305...
21(chain B and (resid 135 through 303 or resid 305...
31(chain C and (resid 135 through 303 or resid 305...
41(chain D and (resid 135 through 303 or resid 305...

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
11SERSERTYRTYR(chain A and (resid 135 through 303 or resid 305...AA135 - 3031 - 169
12GLUGLULEULEU(chain A and (resid 135 through 303 or resid 305...AA305 - 426171 - 292
13ALAALAASPASP(chain A and (resid 135 through 303 or resid 305...AA428 - 432294 - 298
14LEULEUTHRTHR(chain A and (resid 135 through 303 or resid 305...AA434 - 437300 - 303
15LEULEUTYRTYR(chain A and (resid 135 through 303 or resid 305...AA439 - 476305 - 342
21SERSERTYRTYR(chain B and (resid 135 through 303 or resid 305...BB135 - 3031 - 169
22GLUGLULEULEU(chain B and (resid 135 through 303 or resid 305...BB305 - 426171 - 292
23ALAALAASPASP(chain B and (resid 135 through 303 or resid 305...BB428 - 432294 - 298
24LEULEUTHRTHR(chain B and (resid 135 through 303 or resid 305...BB434 - 437300 - 303
25LEULEUTYRTYR(chain B and (resid 135 through 303 or resid 305...BB439 - 476305 - 342
31SERSERTYRTYR(chain C and (resid 135 through 303 or resid 305...CC135 - 3031 - 169
32GLUGLULEULEU(chain C and (resid 135 through 303 or resid 305...CC305 - 426171 - 292
33ALAALAASPASP(chain C and (resid 135 through 303 or resid 305...CC428 - 432294 - 298
34LEULEUTHRTHR(chain C and (resid 135 through 303 or resid 305...CC434 - 437300 - 303
35LEULEUTYRTYR(chain C and (resid 135 through 303 or resid 305...CC439 - 476305 - 342
41SERSERTYRTYR(chain D and (resid 135 through 303 or resid 305...DD135 - 3031 - 169
42GLUGLULEULEU(chain D and (resid 135 through 303 or resid 305...DD305 - 426171 - 292
43ALAALAASPASP(chain D and (resid 135 through 303 or resid 305...DD428 - 432294 - 298
44LEULEUTHRTHR(chain D and (resid 135 through 303 or resid 305...DD434 - 437300 - 303
45LEULEUTYRTYR(chain D and (resid 135 through 303 or resid 305...DD439 - 476305 - 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-KY5 / (2~{R},3~{R},4~{S},5~{R})-2-(6-aminopurin-9-yl)-5-[[3-azanylpropyl-[3-(pyridin-2-ylamino)propyl]amino]methyl]oxolane-3,4-diol


Mass: 457.529 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H31N9O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 688 / 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: 2.39 Å3/Da / Density % sol: 48.44 %
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: 1.86→71.422 Å / Num. obs: 129298 / % possible obs: 100 % / Redundancy: 6.6 % / Biso Wilson estimate: 34.73 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.04 / Rrim(I) all: 0.103 / Net I/σ(I): 9.1
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all
1.86-1.895.31.82963290.3930.8762.032
10.19-71.4225.60.0549310.9940.0250.06

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Processing

Software
NameVersionClassification
PHENIXrefinement
Aimless0.5.32data scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementResolution: 1.86→71.422 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 23.84
RfactorNum. reflection% reflectionSelection details
Rfree0.2199 6444 4.99 %RANDOM
Rwork0.1993 ---
obs0.2004 129154 99.93 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 97.46 Å2 / Biso mean: 44.8777 Å2 / Biso min: 19.87 Å2
Refinement stepCycle: final / Resolution: 1.86→71.422 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10976 0 168 688 11832
Biso mean--50.38 47.73 -
Num. residues----1368
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A6541X-RAY DIFFRACTION8.137TORSIONAL
12B6541X-RAY DIFFRACTION8.137TORSIONAL
13C6541X-RAY DIFFRACTION8.137TORSIONAL
14D6541X-RAY DIFFRACTION8.137TORSIONAL
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 (%)
1.86-1.88110.35711980.351440754273100
1.8811-1.90330.38611990.324940484247100
1.9033-1.92650.34372190.315240134232100
1.9265-1.95090.28692100.301540224232100
1.9509-1.97650.29422320.284240704302100
1.9765-2.00360.28262110.28240244235100
2.0036-2.03220.27372080.269540824290100
2.0322-2.06260.28612120.266340604272100
2.0626-2.09480.27262290.259940304259100
2.0948-2.12920.27052290.247740254254100
2.1292-2.16590.23322240.242740464270100
2.1659-2.20530.24681900.232841014291100
2.2053-2.24770.26422310.231840574288100
2.2477-2.29360.26221970.22940704267100
2.2936-2.34340.26491930.226241014294100
2.3434-2.3980.24212090.221240164225100
2.398-2.45790.23952160.221640894305100
2.4579-2.52440.2582210.217540984319100
2.5244-2.59870.2462090.213240724281100
2.5987-2.68260.24462000.21240824282100
2.6826-2.77840.21782500.206340494299100
2.7784-2.88970.2222260.198640994325100
2.8897-3.02120.2182390.199740864325100
3.0212-3.18050.19872180.199641054323100
3.1805-3.37970.22582110.19241004311100
3.3797-3.64070.19791970.17741714368100
3.6407-4.0070.20682210.17141254346100
4.007-4.58680.17062030.156342034406100
4.5868-5.77850.18412170.163342274444100
5.7785-71.47440.19292250.1874364458999
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)
12.4671-0.4890.12021.5051-0.47121.7711-0.0418-0.1149-0.2171-0.05910.07440.08880.4264-0.1461-0.01670.7342-0.1345-0.04330.60440.01890.3944-14.05777.1274-71.7251
20.77270.4224-0.36150.9389-0.35670.7970.0784-0.06280.02380.0024-0.04860.21130.2815-0.298-0.02390.5422-0.1095-0.05530.5257-0.01180.3497-14.828726.7867-86.5289
31.16870.66950.14472.3307-0.23490.57530.0663-0.10640.1253-0.1465-0.11760.2858-0.0273-0.20740.06340.5698-0.1017-0.09920.602-0.06090.373-20.931830.1682-88.022
41.78960.3045-0.0421.63950.3551.99030.04320.2458-0.2334-0.1702-0.09590.13850.1606-0.09910.06130.29470.0711-0.0410.2794-0.07860.302317.34929.2407-30.0315
50.9704-0.1699-0.25950.05010.08110.50060.09640.00120.0732-0.055-0.0384-0.00660.02910.0673-0.0670.22070.0147-0.02170.2045-0.00760.30799.869535.7239-14.8191
61.0628-0.0668-0.00662.67150.2411.067-0.03260.0343-0.03-0.0099-0.0085-0.22860.07010.16260.03340.20270.0572-0.04770.3044-0.03240.26923.887227.2608-17.8842
70.8586-0.46570.16942.66220.50251.58530.0332-0.02540.02720.0399-0.0523-0.0796-0.10910.05910.00570.19390.0256-0.04190.2331-0.00410.253622.120932.0269-15.4427
81.4426-0.16390.64281.7982-0.36111.72190.16970.0676-0.0686-0.0199-0.0821-0.12820.21420.2352-0.08370.58290.0886-0.00920.5279-0.04010.332918.635831.1366-92.7599
91.19690.56450.35730.30580.10430.14810.2335-0.28370.10690.1481-0.1367-0.0228-0.02960.0097-0.06690.59820.0421-0.0470.6021-0.03970.39057.773122.2725-64.9596
100.8435-0.0582-0.56090.6847-1.04812.78190.0108-0.08260.0087-0.0976-0.0540.04290.0030.21210.05040.54670.0388-0.09660.571-0.06090.36120.015426.3943-67.1841
111.17420.39210.36391.31430.57292.18450.1452-0.0716-0.1131-0.0230.0288-0.06020.2191-0.0349-0.15610.246-0.0498-0.05310.20410.03840.2948-17.254429.7748-11.053
121.6567-0.51820.50230.38970.00820.28060.3150.5163-0.114-0.2018-0.19160.03940.06670.1076-0.09980.37570.0271-0.0770.3710.00450.3077-5.963321.9211-38.8437
132.62740.5147-0.75521.31260.62712.80230.09950.1198-0.1533-0.0308-0.10020.0531-0.0313-0.0056-0.01640.28390.0183-0.09990.2869-0.00710.3335-20.517126.0908-33.1476
141.30530.023-0.40610.92640.60732.41930.08230.3208-0.0451-0.1538-0.0089-0.07260.1562-0.009-0.08490.3334-0.0148-0.08050.35530.04110.313-19.438525.7826-37.03
151.92770.8316-0.13522.26880.41962.63440.21760.0578-0.05750.1072-0.2208-0.36210.17510.0656-0.03240.45370.086-0.07240.46660.00230.4453-11.303320.7087-40.1632
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 368 )A253 - 368
3X-RAY DIFFRACTION3chain 'A' and (resid 369 through 476 )A369 - 476
4X-RAY DIFFRACTION4chain 'B' and (resid 135 through 278 )B135 - 278
5X-RAY DIFFRACTION5chain 'B' and (resid 279 through 335 )B279 - 335
6X-RAY DIFFRACTION6chain 'B' and (resid 336 through 368 )B336 - 368
7X-RAY DIFFRACTION7chain 'B' and (resid 369 through 476 )B369 - 476
8X-RAY DIFFRACTION8chain 'C' and (resid 135 through 278 )C135 - 278
9X-RAY DIFFRACTION9chain 'C' and (resid 279 through 335 )C279 - 335
10X-RAY DIFFRACTION10chain 'C' and (resid 336 through 476 )C336 - 476
11X-RAY DIFFRACTION11chain 'D' and (resid 135 through 278 )D135 - 278
12X-RAY DIFFRACTION12chain 'D' and (resid 279 through 335 )D279 - 335
13X-RAY DIFFRACTION13chain 'D' and (resid 336 through 368 )D336 - 368
14X-RAY DIFFRACTION14chain 'D' and (resid 369 through 456 )D369 - 456
15X-RAY DIFFRACTION15chain 'D' and (resid 457 through 476 )D457 - 476

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