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- PDB-4lvg: Fragment-based Identification of Amides Derived From trans-2-(Pyr... -

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Basic information

Entry
Database: PDB / ID: 4lvg
TitleFragment-based Identification of Amides Derived From trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


nicotinamide phosphoribosyltransferase activity / nicotinamide phosphoribosyltransferase / NAD biosynthesis via nicotinamide riboside salvage pathway / Nicotinamide salvaging / NAD biosynthetic process / : / NPAS4 regulates expression of target genes / BMAL1:CLOCK,NPAS2 activates circadian gene expression / cytokine activity / circadian regulation of gene expression ...nicotinamide phosphoribosyltransferase activity / nicotinamide phosphoribosyltransferase / NAD biosynthesis via nicotinamide riboside salvage pathway / Nicotinamide salvaging / NAD 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-20O / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.702 Å
AuthorsGiannetti, A.M. / Zheng, X. / Skelton, N. / Wang, W. / Bravo, B. / Feng, Y. / Gunzner-Toste, J. / Ho, Y. / Hua, R. / Wang, C. ...Giannetti, A.M. / Zheng, X. / Skelton, N. / Wang, W. / Bravo, B. / Feng, Y. / Gunzner-Toste, J. / Ho, Y. / Hua, R. / Wang, C. / Zhao, Q. / Liederer, B.M. / Liu, Y. / O'Brien, T. / Oeh, J. / Sampath, D. / Shen, Y. / Wang, L. / Wu, H. / Xiao, Y. / Yuen, P. / Zak, M. / Zhao, G. / Dragovich, P.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
Authors: Zheng, X. / Bair, K.W. / Bauer, P. / Baumeister, T. / Bowman, K.K. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Feng, Y. / Han, B. / Ho, Y.C. / Kley, N. / Li, H. / Liang, X. / ...Authors: Zheng, X. / Bair, K.W. / Bauer, P. / Baumeister, T. / Bowman, K.K. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Feng, Y. / Han, B. / Ho, Y.C. / Kley, N. / Li, H. / Liang, X. / Liederer, B.M. / Lin, J. / Ly, J. / O'Brien, T. / Oeh, J. / Oh, A. / Reynolds, D.J. / Sampath, D. / Sharma, G. / Skelton, N. / Smith, C.C. / Tremayne, J. / Wang, L. / Wang, W. / Wang, Z. / Wu, H. / Wu, J. / Xiao, Y. / Yang, G. / Yuen, P.W. / Zak, M. / Dragovich, P.S.
History
DepositionJul 26, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2013Group: Database references
Revision 1.2Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Feb 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)115,83220
Polymers113,8852
Non-polymers1,94718
Water16,322906
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12160 Å2
ΔGint-49 kcal/mol
Surface area32480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.808, 106.860, 83.241
Angle α, β, γ (deg.)90.00, 96.79, 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-20O / (1S,2S)-N-[4-(phenylsulfonyl)phenyl]-2-(pyridin-3-yl)cyclopropanecarboxamide


Mass: 378.444 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18N2O3S
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 6 / 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.: 906 / 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: 2.36 Å3/Da / Density % sol: 47.84 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.6
Details: 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: Jul 5, 2012
RadiationMonochromator: double crystal / 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: 115025 / Num. obs: 110655 / % possible obs: 96.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 1.7→1.73 Å / % possible all: 71.7

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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: 1.702→32.712 Å / SU ML: 0.15 / σ(F): 1.38 / Phase error: 16.38 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1709 5240 5.04 %5% random
Rwork0.1219 ---
all0.1709 115025 --
obs0.1244 103988 90.19 %-
Solvent computationShrinkage radii: 0.86 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 37.399 Å2 / ksol: 0.361 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.6802 Å2-0 Å20.0594 Å2
2---1.1613 Å2-0 Å2
3----1.7839 Å2
Refinement stepCycle: LAST / Resolution: 1.702→32.712 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7519 0 124 906 8549
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0057809
X-RAY DIFFRACTIONf_angle_d0.9610566
X-RAY DIFFRACTIONf_dihedral_angle_d13.0622864
X-RAY DIFFRACTIONf_chiral_restr0.0681149
X-RAY DIFFRACTIONf_plane_restr0.0041334
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.702-1.72180.2447460.16131062X-RAY DIFFRACTION29
1.7218-1.74210.2319680.15841518X-RAY DIFFRACTION41
1.7421-1.76330.23011110.15941830X-RAY DIFFRACTION51
1.7633-1.78570.20571190.16382149X-RAY DIFFRACTION59
1.7857-1.80920.21841260.14862470X-RAY DIFFRACTION68
1.8092-1.83390.21671360.14362741X-RAY DIFFRACTION75
1.8339-1.86010.20881430.1343135X-RAY DIFFRACTION86
1.8601-1.88790.20561920.12183546X-RAY DIFFRACTION98
1.8879-1.91740.19792210.11243571X-RAY DIFFRACTION99
1.9174-1.94880.16522130.10633641X-RAY DIFFRACTION100
1.9488-1.98240.18951820.10063684X-RAY DIFFRACTION100
1.9824-2.01850.18471960.10273614X-RAY DIFFRACTION100
2.0185-2.05730.15171810.10493631X-RAY DIFFRACTION100
2.0573-2.09930.17781700.10263667X-RAY DIFFRACTION100
2.0993-2.14490.17092040.10383617X-RAY DIFFRACTION100
2.1449-2.19480.14942060.1083653X-RAY DIFFRACTION100
2.1948-2.24970.181800.10353678X-RAY DIFFRACTION100
2.2497-2.31050.16271980.1053626X-RAY DIFFRACTION100
2.3105-2.37840.17041820.10923661X-RAY DIFFRACTION100
2.3784-2.45520.18772020.11033634X-RAY DIFFRACTION100
2.4552-2.54290.17851990.11453656X-RAY DIFFRACTION100
2.5429-2.64470.18061890.11883628X-RAY DIFFRACTION100
2.6447-2.7650.1672020.12133673X-RAY DIFFRACTION100
2.765-2.91070.18321900.13343634X-RAY DIFFRACTION100
2.9107-3.09290.16111960.13173668X-RAY DIFFRACTION100
3.0929-3.33150.15552130.13233628X-RAY DIFFRACTION100
3.3315-3.66640.17691900.13553667X-RAY DIFFRACTION100
3.6664-4.1960.14071970.11683668X-RAY DIFFRACTION100
4.196-5.28290.15152010.11943659X-RAY DIFFRACTION100
5.2829-32.7120.16111870.15553739X-RAY DIFFRACTION99

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