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

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Basic information

Entry
Database: PDB / ID: 7bkg
TitleCo-crystal structure of Human Nicotinamide N-methyltransferase (NNMT) with the tricyclic inhibitor (2)
ComponentsNicotinamide N-methyltransferase
KeywordsTRANSFERASE / Methyl Transferase / drug discovery / Inhibitor complex / Nicotinamide / metabolic disorders
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. / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
S-ADENOSYL-L-HOMOCYSTEINE / Chem-U0Z / Nicotinamide N-methyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.326 Å
AuthorsSchreuder, H.A. / Liesum, A.
CitationJournal: Molecules / Year: 2021
Title: Novel Inhibitors of Nicotinamide- N -Methyltransferase for the Treatment of Metabolic Disorders.
Authors: Kannt, A. / Rajagopal, S. / Hallur, M.S. / Swamy, I. / Kristam, R. / Dhakshinamoorthy, S. / Czech, J. / Zech, G. / Schreuder, H. / Ruf, S.
History
DepositionJan 15, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 17, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)128,16312
Polymers125,8644
Non-polymers2,2998
Water11,043613
1
A: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0413
Polymers31,4661
Non-polymers5752
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0413
Polymers31,4661
Non-polymers5752
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0413
Polymers31,4661
Non-polymers5752
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0413
Polymers31,4661
Non-polymers5752
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.935, 62.304, 107.61
Angle α, β, γ (deg.)91.64, 98.25, 111.64
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NNMT / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): DE
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-U0Z / 5,6-dihydro-2-imino-2H,4H-thiazolo(5,4,3-IJ)quinoline / 3-Thia-1-azatricyclo[6.3.1.04,12]dodeca-4,6,8(12)-trien-2-imine


Mass: 190.265 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H10N2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 613 / 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: 2.24 Å3/Da / Density % sol: 45.14 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: Human NNMT was crystallized using the following conditions: A protein solution with 6 mg/ml NNMT, 50 mM Tris/HCL, pH 8.0, 1 mM DTT, 86uM S-Adenosyl-L-Homocysteine (SAH), 0.95mM ligand and 5% ...Details: Human NNMT was crystallized using the following conditions: A protein solution with 6 mg/ml NNMT, 50 mM Tris/HCL, pH 8.0, 1 mM DTT, 86uM S-Adenosyl-L-Homocysteine (SAH), 0.95mM ligand and 5% v/v glycerol was equilibrated at room temperature in a hanging drop setup against 2.2 M ammonium sulfate with 0.1 M HEPES/Na, pH 7.6. Small crystal appeared after 1-2 weeks.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Jun 29, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.326→106.079 Å / Num. obs: 45768 / % possible obs: 97.5 % / Redundancy: 1.8 % / Rmerge(I) obs: 0.059 / Rpim(I) all: 0.059 / Rrim(I) all: 0.084 / Net I/σ(I): 8
Reflection shellResolution: 2.326→2.334 Å / Redundancy: 1.7 % / Rmerge(I) obs: 0.348 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 447 / Rpim(I) all: 0.348 / Rrim(I) all: 0.492 / % possible all: 96.8

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (6-FEB-2020)refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2iip

2iip


Resolution: 2.326→57.69 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.89 / SU R Cruickshank DPI: 0.393 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.403 / SU Rfree Blow DPI: 0.243 / SU Rfree Cruickshank DPI: 0.245
RfactorNum. reflection% reflectionSelection details
Rfree0.2361 2298 -RANDOM
Rwork0.1752 ---
obs0.1783 45766 97.4 %-
Displacement parametersBiso mean: 33.21 Å2
Baniso -1Baniso -2Baniso -3
1--3.9564 Å20.6922 Å2-3.297 Å2
2--9.3602 Å20.9564 Å2
3----5.4038 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 2.326→57.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8160 0 156 613 8929
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0088581HARMONIC2
X-RAY DIFFRACTIONt_angle_deg111646HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2957SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1462HARMONIC5
X-RAY DIFFRACTIONt_it8581HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1089SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies4HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact7818SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.35
X-RAY DIFFRACTIONt_other_torsion18.34
LS refinement shellResolution: 2.33→2.34 Å
RfactorNum. reflection% reflection
Rfree0.32 38 -
Rwork0.1947 --
obs0.1998 916 94.2 %

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