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- PDB-4n9b: Fragment-based Design of 3-Aminopyridine-derived Amides as Potent... -

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Basic information

Entry
Database: PDB / ID: 4n9b
TitleFragment-based Design of 3-Aminopyridine-derived Amides as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)
ComponentsNicotinamide phosphoribosyltransferase
Keywordstransferase/transferase inhibitor / transferase-transferase inhibitor complex
Function / homology
Function and homology information


nicotinamide phosphoribosyltransferase / nicotinamide phosphoribosyltransferase activity / : / Nicotinamide salvage / NAD+ biosynthetic process / : / NPAS4 regulates expression of target genes / BMAL1:CLOCK,NPAS2 activates circadian expression / cytokine activity / circadian regulation of gene expression ...nicotinamide phosphoribosyltransferase / nicotinamide phosphoribosyltransferase activity / : / Nicotinamide salvage / NAD+ biosynthetic process / : / NPAS4 regulates expression of target genes / BMAL1:CLOCK,NPAS2 activates circadian 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-2HH / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.859 Å
AuthorsDragovich, P.S. / Zhao, G. / Baumeister, T. / Bravo, B. / Giannetti, A.M. / Ho, Y. / Hua, R. / Li, G. / Liang, X. / O'Brien, T. ...Dragovich, P.S. / Zhao, G. / Baumeister, T. / Bravo, B. / Giannetti, A.M. / Ho, Y. / Hua, R. / Li, G. / Liang, X. / O'Brien, T. / Skelton, N.J. / Wang, C. / Zhai, Q. / Oh, A. / Wang, W. / Wang, Y. / Xiao, Y. / Yuen, P. / Zak, M. / Zheng, X.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
Authors: Dragovich, P.S. / Zhao, G. / Baumeister, T. / Bravo, B. / Giannetti, A.M. / Ho, Y.C. / Hua, R. / Li, G. / Liang, X. / Ma, X. / O'Brien, T. / Oh, A. / Skelton, N.J. / Wang, C. / Wang, W. / ...Authors: Dragovich, P.S. / Zhao, G. / Baumeister, T. / Bravo, B. / Giannetti, A.M. / Ho, Y.C. / Hua, R. / Li, G. / Liang, X. / Ma, X. / O'Brien, T. / Oh, A. / Skelton, N.J. / Wang, C. / Wang, W. / Wang, Y. / Xiao, Y. / Yuen, P.W. / Zak, M. / Zhao, Q. / Zheng, X.
History
DepositionOct 20, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 19, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.name / _software.version
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)114,4796
Polymers113,8852
Non-polymers5944
Water1448
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8900 Å2
ΔGint-56 kcal/mol
Surface area33070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.132, 106.313, 83.264
Angle α, β, γ (deg.)90.00, 96.27, 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-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-2HH / 1-methyl-N-(pyridin-3-yl)-1H-pyrazole-5-carboxamide


Mass: 202.213 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H10N4O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / 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: 47.05 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.6
Details: crystals were grown from 0.2uL + 0.2uL drops containing 6mg/mL Nampt, 0.1M Sodium phosphate, 25-29% polyethylene glycol 3350, 0.2M NaCl, 1mM compound, pH 8.6, VAPOR DIFFUSION, HANGING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.977408 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 5, 2012
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977408 Å / Relative weight: 1
ReflectionResolution: 2.85→50 Å / Num. all: 24001 / Num. obs: 24001 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 2.85→2.95 Å / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.7.3_928refinement
PHASERphasing
REFMAC5.5.0110refinement
DENZOdata reduction
SCALEPACKdata scaling
HKL-2000data collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3DHF

3dhf


Resolution: 2.859→46.126 Å / Cor.coef. Fo:Fc: 0.846 / Cor.coef. Fo:Fc free: 0.817 / SU ML: 0.4 / σ(F): 0 / Phase error: 27.99 / Stereochemistry target values: ML / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rfree0.2844 1224 5.12 %
Rwork0.2339 --
obs0.2365 23903 98.92 %
all-24001 -
Solvent computationShrinkage radii: 0.86 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 0 Å2 / ksol: 0.315 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-6.5767 Å2-0 Å21.2129 Å2
2--4.3311 Å20 Å2
3---2.2427 Å2
Refinement stepCycle: LAST / Resolution: 2.859→46.126 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7510 0 40 8 7558
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027726
X-RAY DIFFRACTIONf_angle_d0.58510466
X-RAY DIFFRACTIONf_dihedral_angle_d11.0972844
X-RAY DIFFRACTIONf_chiral_restr0.0411144
X-RAY DIFFRACTIONf_plane_restr0.0031330
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8592-2.97370.31741430.22672332X-RAY DIFFRACTION93
2.9737-3.1090.29141440.20862506X-RAY DIFFRACTION100
3.109-3.27290.29761320.22852557X-RAY DIFFRACTION100
3.2729-3.47790.29121300.242533X-RAY DIFFRACTION100
3.4779-3.74630.29071450.23752528X-RAY DIFFRACTION100
3.7463-4.12310.27791220.22972530X-RAY DIFFRACTION100
4.1231-4.71920.2691380.21632544X-RAY DIFFRACTION99
4.7192-5.94370.26551280.24292575X-RAY DIFFRACTION100
5.9437-46.13180.28671420.25812574X-RAY DIFFRACTION99

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