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

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Basic information

Entry
Database: PDB / ID: 7nbj
TitleCo-crystal structure of Human Nicotinamide N-methyltransferase (NNMT) with the bisubstrate-like inhibitor (1)
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 / : / positive regulation of gluconeogenesis / methylation / 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-U7H / Nicotinamide N-methyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.275 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 27, 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

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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)127,7789
Polymers125,8644
Non-polymers1,9145
Water11,818656
1
A: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0143
Polymers31,4661
Non-polymers5482
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9222
Polymers31,4661
Non-polymers4561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9222
Polymers31,4661
Non-polymers4561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9222
Polymers31,4661
Non-polymers4561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.434, 62.347, 108.387
Angle α, β, γ (deg.)92.23, 97.63, 112.06
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 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P40261, nicotinamide N-methyltransferase
#2: Chemical
ChemComp-U7H / 2-hydroxy-1-(4-(isoquinolin-5-yl)piperazin-1-yl)-2-methyl-3-(3-methyl-4-phenyl-1H-pyrazol-1-yl)propan-1-one / (2~{S})-1-(4-isoquinolin-5-ylpiperazin-1-yl)-2-methyl-3-(3-methyl-4-phenyl-pyrazol-1-yl)-2-oxidanyl-propan-1-one


Mass: 455.551 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H29N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 656 / 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: 2.28 Å3/Da / Density % sol: 46.04 %
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, 0.95mM inhibitor and 5% v/v glycerol was equilibrated at ...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, 0.95mM inhibitor 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 6M-F / Detector: PIXEL / Date: Mar 7, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.275→57.512 Å / Num. obs: 49674 / % possible obs: 97.4 % / Redundancy: 1.8 % / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.071 / Rrim(I) all: 0.1 / Net I/σ(I): 5.9
Reflection shellResolution: 2.275→2.283 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.376 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 483 / Rpim(I) all: 0.376 / Rrim(I) all: 0.532 / % possible all: 96.4

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (6-FEB-2020)refinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 7BK6

7bk6


Resolution: 2.275→57.51 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.909 / SU R Cruickshank DPI: 0.309 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.316 / SU Rfree Blow DPI: 0.212 / SU Rfree Cruickshank DPI: 0.214
RfactorNum. reflection% reflectionSelection details
Rfree0.22 2532 -RANDOM
Rwork0.1687 ---
obs0.1713 49669 97.3 %-
Displacement parametersBiso mean: 31.17 Å2
Baniso -1Baniso -2Baniso -3
1--3.98 Å22.4696 Å2-1.0107 Å2
2--3.7764 Å2-1.3018 Å2
3---0.2037 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: LAST / Resolution: 2.275→57.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8104 0 142 656 8902
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0088463HARMONIC2
X-RAY DIFFRACTIONt_angle_deg111481HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2917SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1396HARMONIC5
X-RAY DIFFRACTIONt_it8463HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1060SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies4HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact7396SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.54
X-RAY DIFFRACTIONt_other_torsion17.67
LS refinement shellResolution: 2.275→2.29 Å
RfactorNum. reflection% reflection
Rfree0.2697 46 -
Rwork0.1968 --
obs--93.27 %

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