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- PDB-7et7: Co-crystal structure of Human Nicotinamide N-methyltransferase (N... -

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Basic information

Entry
Database: PDB / ID: 7et7
TitleCo-crystal structure of Human Nicotinamide N-methyltransferase (NNMT) with tricyclic small molecule inhibitor JBSNF-000028
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 / response to organonitrogen compound / 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-JCU / S-ADENOSYL-L-HOMOCYSTEINE / Nicotinamide N-methyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 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 12, 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

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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)127,23312
Polymers124,9474
Non-polymers2,2878
Water55831
1
A: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8083
Polymers31,2371
Non-polymers5722
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8083
Polymers31,2371
Non-polymers5722
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8083
Polymers31,2371
Non-polymers5722
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8083
Polymers31,2371
Non-polymers5722
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)60.934, 62.862, 75.600
Angle α, β, γ (deg.)108.031, 103.540, 104.252
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
#3: Chemical
ChemComp-JCU / 10-methyl-1,10-diazatricyclo[6.3.1.0^{4,12}]dodeca-4,6,8(12)-trien-11-imine


Mass: 187.241 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H13N3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / 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: 1.99 Å3/Da / Density % sol: 38.25 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 0.2 M Sodium chloride, 0.1 M BIS-TRIS pH 5.8, 25 %(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: 0.95372 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: 0.95372 Å / Relative weight: 1
ReflectionResolution: 2.61→40.42 Å / Num. obs: 28890 / % possible obs: 97.5 % / Redundancy: 2 % / CC1/2: 0.981 / Rmerge(I) obs: 0.106 / Rpim(I) all: 0.106 / Rrim(I) all: 0.149 / Net I/σ(I): 3.3
Reflection shellResolution: 2.61→2.73 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.465 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 3396 / CC1/2: 0.6 / Rpim(I) all: 0.465 / % possible all: 93.1

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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: 2.61→40.42 Å / Cor.coef. Fo:Fc: 0.916 / Cor.coef. Fo:Fc free: 0.846 / SU B: 22.426 / SU ML: 0.454 / Cross valid method: FREE R-VALUE / ESU R Free: 0.415
Details: Hydrogens have been used if present in the input file
RfactorNum. reflection% reflection
Rfree0.2833 1455 5.039 %
Rwork0.2231 27422 -
all0.226 --
obs-28890 97.5 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 38.825 Å2
Baniso -1Baniso -2Baniso -3
1--2.477 Å2-0.363 Å20.449 Å2
2---1.519 Å20.56 Å2
3---2.182 Å2
Refinement stepCycle: LAST / Resolution: 2.61→40.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8128 0 56 31 8215
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0128383
X-RAY DIFFRACTIONr_scangle_it2.8295.8266250
X-RAY DIFFRACTIONr_lrange_it4.68451.81412639
LS refinement shellResolution: 2.61→2.73 Å /
Num. reflection% reflection
Rwork1870 -
obs-93.1 %

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