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- PDB-4jnm: Discovery of Potent and Efficacious Urea-containing Nicotinamide ... -

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Basic information

Entry
Database: PDB / ID: 4jnm
TitleDiscovery of Potent and Efficacious Urea-containing Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors with Reduced CYP2C9 Inhibition Properties
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTransferase/Transferase inhibitor / Transferase-Transferase inhibitor complex
Function / homology
Function and homology information


nicotinamide phosphoribosyltransferase / nicotinamide phosphoribosyltransferase activity / NAD biosynthesis via nicotinamide riboside salvage pathway / Nicotinamide salvaging / NAD biosynthetic process / positive regulation of nitric-oxide synthase biosynthetic process / NPAS4 regulates expression of target genes / BMAL1:CLOCK,NPAS2 activates circadian gene expression / cytokine activity / circadian regulation of gene expression ...nicotinamide phosphoribosyltransferase / nicotinamide phosphoribosyltransferase activity / NAD biosynthesis via nicotinamide riboside salvage pathway / Nicotinamide salvaging / NAD biosynthetic process / positive regulation of nitric-oxide synthase biosynthetic process / NPAS4 regulates expression of target genes / BMAL1:CLOCK,NPAS2 activates circadian gene expression / cytokine activity / circadian regulation of gene expression / cell junction / cell-cell signaling / nuclear speck / positive regulation of cell population proliferation / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular exosome / identical protein binding / cytosol
Similarity search - Function
Nicotinamide phosphoribosyl transferase / Nicotinamide phosphoribosyltransferase, N-terminal domain / Nicotinamide phosphoribosyltransferase, N-terminal domain / Nicotinate/nicotinamide phosphoribosyltransferase / Nicotinate phosphoribosyltransferase (NAPRTase) family / Nicotinate phosphoribosyltransferase-like, C-terminal / Aldolase class I / Aldolase-type TIM barrel / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-1LJ / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsGunzner-Toste, J. / Zhao, G. / Bauer, P. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Fu, B. / Han, B. / Ho, Y. ...Gunzner-Toste, J. / Zhao, G. / Bauer, P. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Fu, B. / Han, B. / Ho, Y. / Kley, N. / Liederer, B. / Lin, J. / Mukadam, S. / O'Brien, T. / Reynolds, D.J. / Sharma, G. / Skelton, N. / Smith, C.C. / Oh, A. / Wang, W. / Wang, Z. / Xiao, Y. / Yuen, P. / Zak, M. / Zhang, L. / Zheng, X. / Bair, K.W. / Dragovich, P.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties.
Authors: Gunzner-Toste, J. / Zhao, G. / Bauer, P. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Fu, B. / Han, B. / Ho, Y.C. / Kley, N. / Liang, X. / Liederer, B.M. / Lin, J. ...Authors: Gunzner-Toste, J. / Zhao, G. / Bauer, P. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Fu, B. / Han, B. / Ho, Y.C. / Kley, N. / Liang, X. / Liederer, B.M. / Lin, J. / Mukadam, S. / O'Brien, T. / Oh, A. / Reynolds, D.J. / Sharma, G. / Skelton, N. / Smith, C.C. / Sodhi, J. / Wang, W. / Wang, Z. / Xiao, Y. / Yuen, P.W. / Zak, M. / Zhang, L. / Zheng, X. / Bair, K.W. / Dragovich, P.S.
History
DepositionMar 15, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nicotinamide phosphoribosyltransferase
B: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,65018
Polymers113,8852
Non-polymers1,76516
Water10,863603
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11720 Å2
ΔGint-34 kcal/mol
Surface area32600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.440, 106.323, 82.824
Angle α, β, γ (deg.)90.00, 96.34, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Nicotinamide phosphoribosyltransferase / NAmPRTase / Nampt / Pre-B-cell colony-enhancing factor 1 / Pre-B cell-enhancing factor / Visfatin


Mass: 56942.375 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NAMPT, PBEF, PBEF1 / Production host: Escherichia coli (E. coli)
References: UniProt: P43490, nicotinamide phosphoribosyltransferase
#2: Chemical ChemComp-1LJ / 1-[(6-aminopyridin-3-yl)methyl]-3-[4-(phenylsulfonyl)phenyl]urea


Mass: 382.436 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H18N4O3S
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 603 / Source method: isolated from a natural source / Formula: H2O

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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: 2.32 Å3/Da / Density % sol: 47.04 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop
Details: 0.2uL + 0.2uL drops containing 6mg/mL Nampt, 0.1M Sodium phosphate, 25-29% polyethylene glycol 3350, 0.2M NaCl, 1mM compound, VAPOR DIFFUSION, HANGING DROP, temperature 292K
PH range: 8.6-9.0

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Oct 23, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. all: 52863 / Num. obs: 49268 / % possible obs: 93.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 1 / Redundancy: 3.3 % / Rmerge(I) obs: 0.149
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 2.2 % / Mean I/σ(I) obs: 2.1 / Rsym value: 0.44 / % possible all: 62.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→38.383 Å / SU ML: 0.31 / σ(F): 1.33 / Phase error: 26.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2495 2498 5.07 %
Rwork0.2006 --
obs0.2031 49223 92.7 %
all-53009 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 24.137 Å2 / ksol: 0.361 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-17.4358 Å20 Å25.2746 Å2
2--7.4055 Å20 Å2
3---4.1601 Å2
Refinement stepCycle: LAST / Resolution: 2.2→38.383 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7543 0 114 603 8260
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037845
X-RAY DIFFRACTIONf_angle_d0.69510613
X-RAY DIFFRACTIONf_dihedral_angle_d11.172881
X-RAY DIFFRACTIONf_chiral_restr0.051151
X-RAY DIFFRACTIONf_plane_restr0.0031347
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.23860.2907960.25331490X-RAY DIFFRACTION53
2.2386-2.28430.2788950.25091827X-RAY DIFFRACTION67
2.2843-2.3340.35781130.23762088X-RAY DIFFRACTION74
2.334-2.38830.27261110.23242358X-RAY DIFFRACTION85
2.3883-2.4480.30621520.23822629X-RAY DIFFRACTION94
2.448-2.51420.29371530.22072775X-RAY DIFFRACTION99
2.5142-2.58810.29081490.22162745X-RAY DIFFRACTION99
2.5881-2.67170.26711340.22032791X-RAY DIFFRACTION99
2.6717-2.76710.31291490.23152796X-RAY DIFFRACTION99
2.7671-2.87790.30781290.23152799X-RAY DIFFRACTION100
2.8779-3.00880.27431520.23362764X-RAY DIFFRACTION100
3.0088-3.16740.2471760.20442775X-RAY DIFFRACTION100
3.1674-3.36570.2261530.20642802X-RAY DIFFRACTION100
3.3657-3.62540.25041380.19172801X-RAY DIFFRACTION100
3.6254-3.98990.21311510.18062798X-RAY DIFFRACTION100
3.9899-4.56640.20761570.15732795X-RAY DIFFRACTION100
4.5664-5.75010.18421410.17072823X-RAY DIFFRACTION100
5.7501-38.38890.24451490.18192869X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 13.511 Å / Origin y: 1.4191 Å / Origin z: 22.5259 Å
111213212223313233
T-0.0353 Å2-0.0144 Å2-0.0115 Å2--0.0149 Å20.011 Å2---0.0353 Å2
L0.0344 °2-0.0014 °20.0098 °2-0.039 °20.0192 °2--0.0576 °2
S0.0317 Å °-0.0034 Å °0.0142 Å °-0.057 Å °0.0394 Å °-0.0561 Å °-0.0071 Å °0.0455 Å °0.1301 Å °
Refinement TLS groupSelection details: ALL

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