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- PDB-7eu5: Co-crystal structure of Human Nicotinamide N-methyltransferase (N... -

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Basic information

Entry
Database: PDB / ID: 7eu5
TitleCo-crystal structure of Human Nicotinamide N-methyltransferase (NNMT) with tricyclic small molecule inhibitor JBSNF-000107
ComponentsNicotinamide N-methyltransferase
KeywordsTRANSFERASE / NNMT
Function / homology
Function and homology information


pyridine N-methyltransferase activity / nicotinamide N-methyltransferase / nicotinamide metabolic process / nicotinamide N-methyltransferase activity / Metabolism of ingested SeMet, Sec, MeSec into H2Se / positive regulation of protein deacetylation / NAD biosynthesis via nicotinamide riboside salvage pathway / Methylation / Nicotinamide salvaging / animal organ regeneration ...pyridine N-methyltransferase activity / nicotinamide N-methyltransferase / nicotinamide metabolic process / nicotinamide N-methyltransferase activity / Metabolism of ingested SeMet, Sec, MeSec into H2Se / positive regulation of protein deacetylation / NAD biosynthesis via nicotinamide riboside salvage pathway / Methylation / Nicotinamide salvaging / 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. / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
Chem-JDL / S-ADENOSYL-L-HOMOCYSTEINE / Nicotinamide N-methyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.731 Å
AuthorsSwaminathan, S. / Gosu, R. / Birudukota, S. / Kandan, S. / Vaithilingam, K.
CitationJournal: Sci Rep / Year: 2022
Title: Novel tricyclic small molecule inhibitors of Nicotinamide N-methyltransferase for the treatment of metabolic disorders.
Authors: Ruf, S. / Rajagopal, S. / Kadnur, S.V. / Hallur, M.S. / Rani, S. / Kristam, R. / Swaminathan, S. / Zope, B.R. / Gondrala, P.K. / Swamy, I. / Putta, V.P.R.K. / Kandan, S. / Zech, G. / ...Authors: Ruf, S. / Rajagopal, S. / Kadnur, S.V. / Hallur, M.S. / Rani, S. / Kristam, R. / Swaminathan, S. / Zope, B.R. / Gondrala, P.K. / Swamy, I. / Putta, V.P.R.K. / Kandan, S. / Zech, G. / Schreuder, H. / Rudolph, C. / Elvert, R. / Czech, J. / Birudukota, S. / Siddiqui, M.A. / Anand, N.N. / Mane, V.S. / Dittakavi, S. / Suresh, J. / Gosu, R. / Ramesh, M. / Yura, T. / Dhakshinamoorthy, S. / Kannt, A.
History
DepositionMay 16, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 30, 2022Group: Database references / Derived calculations / Category: atom_type / citation / citation_author
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 29, 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

Downloads & links

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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)127,30512
Polymers124,9474
Non-polymers2,3598
Water77543
1
A: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8263
Polymers31,2371
Non-polymers5902
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8263
Polymers31,2371
Non-polymers5902
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8263
Polymers31,2371
Non-polymers5902
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8263
Polymers31,2371
Non-polymers5902
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)60.737, 62.543, 71.491
Angle α, β, γ (deg.)94.214, 103.003, 103.651
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Nicotinamide N-methyltransferase


Mass: 31236.717 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 / Production host: Escherichia coli (E. coli)
References: UniProt: P40261, nicotinamide N-methyltransferase
#2: Chemical
ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Type: L-peptide linking / Mass: 384.411 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H20N6O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-JDL / 6-fluoranyl-10-methyl-1,10-diazatricyclo[6.3.1.0^{4,12}]dodeca-4,6,8(12)-trien-11-imine


Mass: 205.231 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H12FN3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 43 / 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: 2.02 Å3/Da / Density % sol: 39.07 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5.2
Details: 0.2 M Sodium chloride, 0.1 M BIS-TRIS pH 5.2, 24 %(w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 12, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.71→48.73 Å / Num. obs: 25314 / % possible obs: 94.6 % / Redundancy: 1.9 % / CC1/2: 0.923 / Rmerge(I) obs: 0.19 / Net I/σ(I): 3.1
Reflection shellResolution: 2.71→2.84 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.585 / Mean I/σ(I) obs: 1 / Num. unique obs: 2674 / CC1/2: 0.486 / % possible all: 74.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ROD

3rod


Resolution: 2.731→48.73 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.837 / SU B: 25.222 / SU ML: 0.48 / Cross valid method: FREE R-VALUE / ESU R Free: 0.463
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.28 1275 5.109 %
Rwork0.2079 23679 -
all0.212 --
obs-24954 95.284 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 30.051 Å2
Baniso -1Baniso -2Baniso -3
1--2.184 Å2-1.249 Å2-0.342 Å2
2---0.73 Å20.045 Å2
3---3.243 Å2
Refinement stepCycle: LAST / Resolution: 2.731→48.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8019 0 60 43 8122
Refine LS restraintsType: r_lrange_other / Dev ideal: 4.062 / Dev ideal target: 36.367 / Number: 8859

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