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- PDB-4n9c: Fragment-based Design of 3-Aminopyridine-derived Amides as Potent... -

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Basic information

Entry
Database: PDB / ID: 4n9c
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
5-nitro-1H-benzimidazole / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.751 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)114,4016
Polymers113,8852
Non-polymers5164
Water20,4111133
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8770 Å2
ΔGint-54 kcal/mol
Surface area33470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.630, 106.660, 83.170
Angle α, β, γ (deg.)90.00, 96.62, 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-2ZM / 5-nitro-1H-benzimidazole


Mass: 163.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H5N3O2
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1133 / 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: 2.35 Å3/Da / Density % sol: 47.56 %
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: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 18, 2012
RadiationMonochromator: Double-crystal, Si(111) liquid N2 cooled / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. all: 352883 / Num. obs: 350060 / % possible obs: 99.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 1.75→1.756 Å / % possible all: 98.7

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.751→38.52 Å / SU ML: 0.18 / σ(F): 1.33 / Phase error: 19.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.201 4970 5.01 %5 % random
Rwork0.1655 ---
obs0.1673 99159 95.07 %-
all-104806 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.751→38.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7519 0 34 1133 8686
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0067767
X-RAY DIFFRACTIONf_angle_d1.01710530
X-RAY DIFFRACTIONf_dihedral_angle_d12.5422864
X-RAY DIFFRACTIONf_chiral_restr0.0711149
X-RAY DIFFRACTIONf_plane_restr0.0051344
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7505-1.77040.26342900.23256119X-RAY DIFFRACTION92
1.7704-1.79120.29443070.23516131X-RAY DIFFRACTION93
1.7912-1.81310.24393070.22076212X-RAY DIFFRACTION93
1.8131-1.8360.23312770.21356172X-RAY DIFFRACTION92
1.836-1.86020.25663150.21256153X-RAY DIFFRACTION93
1.8602-1.88570.2693620.21696069X-RAY DIFFRACTION93
1.8857-1.91260.24043300.20986169X-RAY DIFFRACTION94
1.9126-1.94110.263100.19376233X-RAY DIFFRACTION94
1.9411-1.97150.21994060.18496112X-RAY DIFFRACTION94
1.9715-2.00380.21553440.17176206X-RAY DIFFRACTION94
2.0038-2.03830.22113550.1756156X-RAY DIFFRACTION94
2.0383-2.07540.22062950.17066296X-RAY DIFFRACTION95
2.0754-2.11530.21073350.17216237X-RAY DIFFRACTION94
2.1153-2.15850.19533110.16476297X-RAY DIFFRACTION95
2.1585-2.20540.19733230.16596286X-RAY DIFFRACTION96
2.2054-2.25670.19193380.15646405X-RAY DIFFRACTION96
2.2567-2.31320.20293770.16016307X-RAY DIFFRACTION96
2.3132-2.37570.2113300.16356410X-RAY DIFFRACTION97
2.3757-2.44560.19933150.15996459X-RAY DIFFRACTION97
2.4456-2.52450.18383540.15926435X-RAY DIFFRACTION98
2.5245-2.61470.22053690.16256374X-RAY DIFFRACTION98
2.6147-2.71940.19212920.1586474X-RAY DIFFRACTION97
2.7194-2.84310.19863660.16826349X-RAY DIFFRACTION97
2.8431-2.99290.22713260.17196396X-RAY DIFFRACTION96
2.9929-3.18040.20353320.15566348X-RAY DIFFRACTION96
3.1804-3.42580.193270.15486296X-RAY DIFFRACTION96
3.4258-3.77030.18663430.1526254X-RAY DIFFRACTION95
3.7703-4.31520.14962920.14066064X-RAY DIFFRACTION92
4.3152-5.43430.16273690.13696418X-RAY DIFFRACTION97
5.4343-38.52910.19533430.17096542X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 12.1094 Å / Origin y: -0.2065 Å / Origin z: 18.5517 Å
111213212223313233
T0.0253 Å20.0031 Å2-0.0018 Å2-0.0368 Å20.0026 Å2--0.0384 Å2
L0.1303 °2-0.0271 °2-0.0305 °2-0.2129 °20.0228 °2--0.1904 °2
S0.0233 Å °0.0154 Å °-0.0022 Å °0.0245 Å °0.0012 Å °0.0255 Å °-0.0021 Å °-0.051 Å °0.0359 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 8:486 ) OR ( CHAIN B AND RESID 8:487 )A8 - 486
2X-RAY DIFFRACTION1( CHAIN A AND RESID 8:486 ) OR ( CHAIN B AND RESID 8:487 )B8 - 487

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