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- PDB-6chh: Structure of human NNMT in complex with bisubstrate inhibitor MS2756 -

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Basic information

Entry
Database: PDB / ID: 6chh
TitleStructure of human NNMT in complex with bisubstrate inhibitor MS2756
ComponentsNicotinamide N-methyltransferase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein-small molecule bisubstrate inhibitor complex / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


pyridine N-methyltransferase activity / nicotinamide N-methyltransferase / nicotinamide N-methyltransferase activity / nicotinamide metabolic process / positive regulation of protein deacetylation / Metabolism of ingested SeMet, Sec, MeSec into H2Se / : / Methylation / Nicotinamide salvage / animal organ regeneration ...pyridine N-methyltransferase activity / nicotinamide N-methyltransferase / nicotinamide N-methyltransferase activity / nicotinamide metabolic process / positive regulation of protein deacetylation / Metabolism of ingested SeMet, Sec, MeSec into H2Se / : / Methylation / Nicotinamide salvage / animal organ regeneration / positive regulation of gluconeogenesis / methylation / response to xenobiotic stimulus / cytosol
Similarity search - Function
Methyltransferase, NNMT/PNMT/TEMT / Methyltransferase NNMT/PNMT/TEMT, conserved site / : / NNMT/PNMT/TEMT family / NNMT/PNMT/TEMT family of methyltransferases signature. / SAM-dependent methyltransferase NNMT/PNMT/TEMT-type profile. / Vaccinia Virus protein VP39 / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-F0P / Nicotinamide N-methyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsBabault, N. / Liu, J. / Jin, J.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM122749 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA218600 United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)R01HD088626 United States
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT).
Authors: Babault, N. / Allali-Hassani, A. / Li, F. / Fan, J. / Yue, A. / Ju, K. / Liu, F. / Vedadi, M. / Liu, J. / Jin, J.
History
DepositionFeb 22, 2018Deposition site: RCSB / Processing site: RCSB
SupersessionJun 13, 2018ID: 6B1A
Revision 1.0Jun 13, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Apr 27, 2022Group: Database references / Category: database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 4, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Nicotinamide N-methyltransferase
B: Nicotinamide N-methyltransferase
C: Nicotinamide N-methyltransferase
D: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,10310
Polymers125,8644
Non-polymers2,2386
Water4,071226
1
A: Nicotinamide N-methyltransferase
C: Nicotinamide N-methyltransferase
D: Nicotinamide N-methyltransferase
hetero molecules

B: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,10310
Polymers125,8644
Non-polymers2,2386
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_545x,y-1,z1
Buried area5150 Å2
ΔGint-23 kcal/mol
Surface area39940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.440, 62.560, 107.979
Angle α, β, γ (deg.)91.760, 98.050, 111.830
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Nicotinamide N-methyltransferase


Mass: 31466.033 Da / Num. of mol.: 4 / Mutation: K100A, E101A, E103A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NNMT / Plasmid: pET28a-LIC / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): RIL
References: UniProt: P40261, nicotinamide N-methyltransferase
#2: Chemical
ChemComp-F0P / (2~{S})-5-[2-(3-aminocarbonylphenyl)ethyl-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl]amino]-2-azanyl-pentanoic acid


Mass: 528.561 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H32N8O6
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 226 / Source method: isolated from a natural source / Formula: H2O

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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: 2.28 Å3/Da / Density % sol: 46.09 %
Crystal growTemperature: 290.15 K / Method: vapor diffusion, hanging drop / pH: 7.2 / Details: 1.5 ammonium sulfate, 0.1 M HEPES pH 7.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 19, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.3→106.481 Å / Num. all: 44070 / Num. obs: 44070 / % possible obs: 89.1 % / Redundancy: 3.3 % / Biso Wilson estimate: 20.97 Å2 / Rpim(I) all: 0.088 / Rrim(I) all: 0.167 / Rsym value: 0.141 / Net I/av σ(I): 4.1 / Net I/σ(I): 7.9 / Num. measured all: 147482
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
2.3-2.423.30.5830.966140.3650.6890.58391.6
2.42-2.573.30.4181.462120.2630.4940.41890.9
2.57-2.753.30.2882.158170.1810.3410.28890
2.75-2.973.30.2122.951540.1340.2520.21286.9
2.97-3.253.20.1384.543520.090.1660.13879.1
3.25-3.643.50.0976.646620.060.1140.09793.6
3.64-4.23.50.0797.940900.0490.0930.07993.1
4.2-5.143.40.0728.233560.0450.0850.07290.8
5.14-7.273.30.0827.223200.0530.0980.08281.6
7.27-53.243.40.0696.814930.0440.0820.06995.4

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
PHENIX1.13_2998refinement
PDB_EXTRACT3.24data extraction
PHASERphasing
iMOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2IIP

2iip


Resolution: 2.3→53.24 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.98 / Phase error: 23.81
RfactorNum. reflection% reflection
Rfree0.2289 2037 4.62 %
Rwork0.1677 --
obs0.1705 44056 89.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 119.75 Å2 / Biso mean: 28.47 Å2 / Biso min: 5 Å2
Refinement stepCycle: final / Resolution: 2.3→53.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7971 0 160 226 8357
Biso mean--21.28 27.49 -
Num. residues----1023
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3-2.35350.31161320.20072854298692
2.3535-2.41240.27871330.19142916304991
2.4124-2.47760.27371430.18272855299891
2.4776-2.55050.26661580.1852817297591
2.5505-2.63280.26271490.17242863301291
2.6328-2.72690.23971300.17332849297989
2.7269-2.83610.2581440.16982767291189
2.8361-2.96520.24791340.17332653278786
2.9652-3.12150.23821260.17072597272382
3.1215-3.3170.24881360.17962527266380
3.317-3.57310.2221330.16072933306694
3.5731-3.93260.2081390.1532964310394
3.9326-4.50140.17951520.14672897304993
4.5014-5.67020.19361150.15452765288087
5.6702-53.25450.20861130.17822762287588
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)
10.25120.6210.44492.81362.17832.0566-0.16560.25470.0604-0.46590.12980.0724-0.55730.02670.02670.23330.0099-0.03490.17860.03320.1379-4.67782.5076-19.7148
21.71260.0060.25871.1067-0.4392.0820.1691-0.17850.04570.0917-0.00430.3652-0.0552-0.2828-0.09840.0772-0.02480.00820.169-0.02510.1669-10.54852.07933.752
31.3159-0.1774-0.5370.93650.1790.80.1111-0.15030.0550.1665-0.1289-0.08040.04510.03480.03470.1415-0.037-0.02570.11930.020.15824.51563.23155.9901
41.43550.3373-0.20341.45340.3641.44230.1163-0.13810.32580.2079-0.05290.0936-0.3989-0.16760.05970.1862-0.009-0.00340.1151-0.01570.2034-4.358711.98686.956
51.00730.00370.00830.7256-0.39480.46320.09510.06920.02640.0261-0.1032-0.1922-0.02210.1524-0.00240.068-0.0214-0.02780.11850.02490.16887.4661-0.1998-0.9878
61.09240.27570.0210.8695-0.17261.1890.07310.1142-0.1139-0.2133-0.06440.06870.2024-0.0598-0.01210.04860.0147-0.02720.08580.01670.1641-3.779-9.6397-3.9407
70.3846-0.5319-0.38182.46951.40742.2385-0.1653-0.2683-0.03180.60.16380.14320.42210.0933-0.02660.1931-0.02540.04210.1570.01750.2275-27.967819.4436-4.4035
81.98940.1935-0.21360.6262-0.11261.77330.18130.157-0.0822-0.0733-0.12780.29440.0169-0.1578-0.04050.13780.05120.01910.1234-0.05380.1884-32.940820.2102-27.7513
91.5972-0.00870.68171.10150.05931.25120.06120.22480.0595-0.0689-0.0687-0.0984-0.09260.0532-0.01920.1130.020.03340.1309-0.00260.1896-18.492518.8281-30.0365
101.1823-0.32690.2741.5906-0.05621.25190.0570.1257-0.1022-0.2545-0.15480.10620.5405-0.17960.08880.1962-0.0197-0.00460.1592-0.02430.2079-27.404710.0076-31.1993
110.99810.28550.32631.35880.60011.90950.06140.0238-0.2046-0.21590.0408-0.19020.10340.1985-0.03060.11790.02230.00270.097-0.01040.199-16.217713.8401-26.3691
121.4373-0.3444-0.39430.6437-0.08721.05890.1064-0.02490.12730.1549-0.1102-0.08750.00050.0556-0.00020.0633-0.00650.02780.09430.02030.2045-20.549826.7726-18.3113
132.0490.5104-0.0780.7591-0.06981.43180.0663-0.20770.15170.0583-0.0262-0.1024-0.3072-0.0312-0.0090.0672-0.01430.01060.08570.00830.2536-24.533234.2885-23.7057
142.2238-0.17970.45971.99320.05161.40950.09440.2595-0.2091-0.3879-0.00750.04450.25460.1464-0.0770.27790.0664-0.02280.2055-0.03340.1296-9.0189-16.2611-48.7026
150.9736-0.1799-0.00620.64910.06552.1253-0.11840.3345-0.2328-0.5470.0504-0.05520.22290.0976-0.2030.53240.1411-0.05820.36-0.0997-0.013-8.1047-18.0511-57.9018
160.81920.06280.23370.91930.00251.10330.06260.0432-0.0206-0.1531-0.04910.2099-0.0621-0.12010.00530.18340.0344-0.04280.1951-0.03220.1403-18.7074-10.2145-44.3342
172.1269-0.1595-0.04891.4691-0.25111.28370.04610.03980.0795-0.0197-0.077-0.0877-0.06440.08920.03180.0858-0.0077-0.02130.13510.03370.1153-6.1214-8.9258-35.7564
182.2871-1.2868-0.48781.9021-0.48053.3938-0.0039-0.59160.13190.18970.0352-0.3361-0.01860.61690.24290.4117-0.0326-0.16480.34160.03830.11450.6288-26.467229.9561
191.1128-0.0727-0.28120.89920.01031.02720.1162-0.19030.20620.4578-0.05940.1211-0.25330.1205-0.01260.3286-0.08060.03710.2151-0.02630.1276-11.1375-17.707727.3093
200.6812-0.11020.00260.90720.04321.0432-0.0285-0.09270.01490.311-0.02750.33330.0085-0.08810.0090.1821-0.03970.0370.1681-0.01160.1426-19.1088-25.75120.1056
211.98750.16020.10191.4661-0.05361.26450.03880.0293-0.091-0.0891-0.038-0.15830.11290.12980.01440.08180.00550.03040.11640.02280.1427-6.3796-27.044911.7853
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid -8 through 16 )A-8 - 16
2X-RAY DIFFRACTION2chain 'A' and (resid 17 through 50 )A17 - 50
3X-RAY DIFFRACTION3chain 'A' and (resid 51 through 87 )A51 - 87
4X-RAY DIFFRACTION4chain 'A' and (resid 88 through 123 )A88 - 123
5X-RAY DIFFRACTION5chain 'A' and (resid 124 through 198 )A124 - 198
6X-RAY DIFFRACTION6chain 'A' and (resid 199 through 262 )A199 - 262
7X-RAY DIFFRACTION7chain 'B' and (resid -8 through 16 )B-8 - 16
8X-RAY DIFFRACTION8chain 'B' and (resid 17 through 50 )B17 - 50
9X-RAY DIFFRACTION9chain 'B' and (resid 51 through 87 )B51 - 87
10X-RAY DIFFRACTION10chain 'B' and (resid 88 through 123 )B88 - 123
11X-RAY DIFFRACTION11chain 'B' and (resid 124 through 150 )B124 - 150
12X-RAY DIFFRACTION12chain 'B' and (resid 151 through 217 )B151 - 217
13X-RAY DIFFRACTION13chain 'B' and (resid 218 through 262 )B218 - 262
14X-RAY DIFFRACTION14chain 'C' and (resid 16 through 87 )C16 - 87
15X-RAY DIFFRACTION15chain 'C' and (resid 88 through 123 )C88 - 123
16X-RAY DIFFRACTION16chain 'C' and (resid 124 through 198 )C124 - 198
17X-RAY DIFFRACTION17chain 'C' and (resid 199 through 261 )C199 - 261
18X-RAY DIFFRACTION18chain 'D' and (resid 16 through 32 )D16 - 32
19X-RAY DIFFRACTION19chain 'D' and (resid 33 through 123 )D33 - 123
20X-RAY DIFFRACTION20chain 'D' and (resid 124 through 198 )D124 - 198
21X-RAY DIFFRACTION21chain 'D' and (resid 199 through 261 )D199 - 261

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