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

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Basic information

Entry
Database: PDB / ID: 7nbq
TitleCo-crystal structure of Human Nicotinamide N-methyltransferase (NNMT) with the tricyclic inhibitor (4)
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
S-ADENOSYL-L-HOMOCYSTEINE / Chem-U72 / Nicotinamide N-methyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.479 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

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)128,20712
Polymers125,8644
Non-polymers2,3438
Water8,773487
1
A: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0523
Polymers31,4661
Non-polymers5862
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0523
Polymers31,4661
Non-polymers5862
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0523
Polymers31,4661
Non-polymers5862
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Nicotinamide N-methyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0523
Polymers31,4661
Non-polymers5862
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.012, 62.306, 107.932
Angle α, β, γ (deg.)91.52, 97.86, 111.66
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) / 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-U72 / 2-methyl-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1-ij]quinazolin-3-imine / 3-methyl-1,3-diazatricyclo[7.3.1.0^{5,13}]trideca-5,7,9(13)-trien-2-imine


Mass: 201.268 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H15N3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 487 / 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: 2.26 Å3/Da / Density % sol: 45.46 %
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 inhibitor and ...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 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: X06SA / Wavelength: 1.00002 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Jun 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 2.479→106.54 Å / Num. obs: 38089 / % possible obs: 97.7 % / Redundancy: 1.8 % / CC1/2: 0.993 / Rmerge(I) obs: 0.072 / Rpim(I) all: 0.072 / Rrim(I) all: 0.101 / Net I/σ(I): 7.4
Reflection shellResolution: 2.48→3.04 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.228 / Mean I/σ(I) obs: 3.2 / Num. unique obs: 17221 / CC1/2: 0.896 / Rpim(I) all: 0.227 / Rrim(I) all: 0.322 / % possible all: 97.2

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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: 7BKG

7bkg


Resolution: 2.479→106.54 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.851 / SU R Cruickshank DPI: 0.802 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.788 / SU Rfree Blow DPI: 0.318 / SU Rfree Cruickshank DPI: 0.324
RfactorNum. reflection% reflectionSelection details
Rfree0.2713 1957 -RANDOM
Rwork0.1912 ---
obs0.1953 38089 97.6 %-
Displacement parametersBiso mean: 34.08 Å2
Baniso -1Baniso -2Baniso -3
1--4.6657 Å2-0.6434 Å2-1.755 Å2
2--6.6702 Å2-1.1713 Å2
3----2.0046 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: LAST / Resolution: 2.479→106.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8086 0 164 487 8737
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0088451HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0211463HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2936SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1436HARMONIC5
X-RAY DIFFRACTIONt_it8451HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1077SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact7242SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.33
X-RAY DIFFRACTIONt_other_torsion19.05
LS refinement shellResolution: 2.48→2.5 Å
RfactorNum. reflection% reflection
Rfree0.2909 43 -
Rwork0.2143 --
obs0.2186 762 94.49 %

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