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- PDB-4n9d: Fragment-based Design of 3-Aminopyridine-derived Amides as Potent... -

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Basic information

Entry
Database: PDB / ID: 4n9d
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 / 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-2HJ / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.701 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. / Zhao, 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 1.1Feb 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)115,29412
Polymers113,8852
Non-polymers1,40910
Water18,6821037
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10190 Å2
ΔGint-30 kcal/mol
Surface area32850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.413, 106.337, 83.205
Angle α, β, γ (deg.)90.00, 96.57, 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-2HJ / 4-({[(4-tert-butylphenyl)sulfonyl]amino}methyl)-N-(pyridin-3-yl)benzamide


Mass: 423.528 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H25N3O3S
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


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


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1037 / 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: 2.33 Å3/Da / Density % sol: 47.24 %
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: 0.97922 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 5, 2012
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97922 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. all: 114870 / Num. obs: 110046 / % possible obs: 95.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 1.7→1.73 Å / % possible all: 73.3

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.701→34.839 Å / SU ML: 0.15 / σ(F): 1.34 / Phase error: 17.52 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1833 5485 5.01 %5% random
Rwork0.1523 ---
obs0.1538 109525 95.76 %-
all-114870 --
Solvent computationShrinkage radii: 0.86 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 40.576 Å2 / ksol: 0.375 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-2.7928 Å2-0 Å20.2208 Å2
2---0.9072 Å2-0 Å2
3----1.8857 Å2
Refinement stepCycle: LAST / Resolution: 1.701→34.839 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7519 0 94 1037 8650
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077823
X-RAY DIFFRACTIONf_angle_d1.08410598
X-RAY DIFFRACTIONf_dihedral_angle_d13.7112882
X-RAY DIFFRACTIONf_chiral_restr0.0751149
X-RAY DIFFRACTIONf_plane_restr0.0061346
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7008-1.72010.21061310.1812439X-RAY DIFFRACTION67
1.7201-1.74040.22081510.18642652X-RAY DIFFRACTION74
1.7404-1.76160.24231320.18362800X-RAY DIFFRACTION78
1.7616-1.78390.24961510.17563006X-RAY DIFFRACTION83
1.7839-1.80730.2221640.17513127X-RAY DIFFRACTION87
1.8073-1.83210.19982070.16423350X-RAY DIFFRACTION92
1.8321-1.85830.23651920.16783465X-RAY DIFFRACTION98
1.8583-1.8860.20052280.1623563X-RAY DIFFRACTION100
1.886-1.91550.21321930.15923576X-RAY DIFFRACTION99
1.9155-1.94690.21531870.15473624X-RAY DIFFRACTION99
1.9469-1.98050.18951820.14823600X-RAY DIFFRACTION100
1.9805-2.01650.18871840.1493608X-RAY DIFFRACTION100
2.0165-2.05520.17531910.14953596X-RAY DIFFRACTION100
2.0552-2.09720.18571780.16093626X-RAY DIFFRACTION100
2.0972-2.14280.19461930.15443624X-RAY DIFFRACTION100
2.1428-2.19260.17472020.15643569X-RAY DIFFRACTION100
2.1926-2.24740.18311860.15543642X-RAY DIFFRACTION100
2.2474-2.30820.19241730.15463638X-RAY DIFFRACTION100
2.3082-2.37610.20251920.15173579X-RAY DIFFRACTION100
2.3761-2.45280.19281840.15193637X-RAY DIFFRACTION100
2.4528-2.54040.19762090.15283619X-RAY DIFFRACTION100
2.5404-2.64210.2041830.1513608X-RAY DIFFRACTION100
2.6421-2.76230.16091740.1523651X-RAY DIFFRACTION100
2.7623-2.90790.18092150.15823584X-RAY DIFFRACTION100
2.9079-3.08990.16691700.15513658X-RAY DIFFRACTION100
3.0899-3.32840.19291900.14883620X-RAY DIFFRACTION100
3.3284-3.6630.17651820.14623653X-RAY DIFFRACTION100
3.663-4.19220.13841830.12863666X-RAY DIFFRACTION100
4.1922-5.27880.13431970.13123624X-RAY DIFFRACTION100
5.2788-34.84670.20911810.17163636X-RAY DIFFRACTION97

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