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- PDB-4kfp: Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived U... -

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Basic information

Entry
Database: PDB / ID: 4kfp
TitleIdentification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived Ureas 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 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-1R7 / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.84 Å
AuthorsDragovich, P.S. / Bair, K.W. / Baumeister, T. / Ho, Y. / Liederer, B.M. / Liu, X. / O'Brien, T. / Oeh, J. / Sampath, D. / Skelton, N. ...Dragovich, P.S. / Bair, K.W. / Baumeister, T. / Ho, Y. / Liederer, B.M. / Liu, X. / O'Brien, T. / Oeh, J. / Sampath, D. / Skelton, N. / Wang, L. / Wang, W. / Wu, H. / Xiao, Y. / Yuen, P. / Zak, M. / Zhang, L. / Zheng, X.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
Authors: Dragovich, P.S. / Bair, K.W. / Baumeister, T. / Ho, Y.C. / Liederer, B.M. / Liu, X. / Liu, Y. / O'Brien, T. / Oeh, J. / Sampath, D. / Skelton, N. / Wang, L. / Wang, W. / Wu, H. / Xiao, Y. / ...Authors: Dragovich, P.S. / Bair, K.W. / Baumeister, T. / Ho, Y.C. / Liederer, B.M. / Liu, X. / Liu, Y. / O'Brien, T. / Oeh, J. / Sampath, D. / Skelton, N. / Wang, L. / Wang, W. / Wu, H. / Xiao, Y. / Yuen, P.W. / Zak, M. / Zhang, L. / Zheng, X.
History
DepositionApr 27, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 21, 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)115,66415
Polymers113,8852
Non-polymers1,78013
Water14,790821
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13120 Å2
ΔGint-44 kcal/mol
Surface area32250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.550, 106.331, 82.931
Angle α, β, γ (deg.)90.00, 96.58, 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-1R7 / N-(4-{[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]sulfonyl}benzyl)-2H-pyrrolo[3,4-c]pyridine-2-carboxamide


Mass: 482.595 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H30N4O4S
#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.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 821 / 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: 47.18 %
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 13, 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: 1.84→50 Å / Num. all: 91043 / Num. obs: 89040 / % possible obs: 97.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.6 % / Rsym value: 0.089 / Net I/σ(I): 13.9
Reflection shellResolution: 1.84→1.91 Å / % possible all: 80

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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: 1.84→36.98 Å / SU ML: 0.17 / σ(F): 0 / Phase error: 16.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1705 4475 5.03 %0.05 Random
Rwork0.1426 ---
obs0.144 89000 98.84 %-
all-91043 --
Solvent computationShrinkage radii: 0.86 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 36.831 Å2 / ksol: 0.364 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-10.9685 Å20 Å22.574 Å2
2--0.7427 Å2-0 Å2
3----0.436 Å2
Refinement stepCycle: LAST / Resolution: 1.84→36.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7524 0 116 821 8461
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077819
X-RAY DIFFRACTIONf_angle_d1.03510581
X-RAY DIFFRACTIONf_dihedral_angle_d12.8822864
X-RAY DIFFRACTIONf_chiral_restr0.0731150
X-RAY DIFFRACTIONf_plane_restr0.0051335
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.84-1.86260.26711060.23341997X-RAY DIFFRACTION71
1.8626-1.88450.24421230.19512867X-RAY DIFFRACTION99
1.8845-1.90750.21951280.17772823X-RAY DIFFRACTION99
1.9075-1.93170.21311460.16342858X-RAY DIFFRACTION99
1.9317-1.95710.21191590.1552786X-RAY DIFFRACTION100
1.9571-1.98390.19321680.1532820X-RAY DIFFRACTION100
1.9839-2.01220.1881400.14012843X-RAY DIFFRACTION99
2.0122-2.04230.20551520.14122840X-RAY DIFFRACTION100
2.0423-2.07420.17511530.14212843X-RAY DIFFRACTION100
2.0742-2.10820.18721500.14132820X-RAY DIFFRACTION100
2.1082-2.14450.18481560.14112824X-RAY DIFFRACTION100
2.1445-2.18350.18721640.14172838X-RAY DIFFRACTION100
2.1835-2.22550.17731530.1342816X-RAY DIFFRACTION100
2.2255-2.27090.16731560.13822831X-RAY DIFFRACTION100
2.2709-2.32030.19941590.13452854X-RAY DIFFRACTION100
2.3203-2.37430.15461600.13682812X-RAY DIFFRACTION100
2.3743-2.43360.17881500.13152874X-RAY DIFFRACTION100
2.4336-2.49940.16671520.13522826X-RAY DIFFRACTION100
2.4994-2.5730.17591550.14092853X-RAY DIFFRACTION100
2.573-2.6560.18931520.14222843X-RAY DIFFRACTION100
2.656-2.75090.16361430.14492858X-RAY DIFFRACTION100
2.7509-2.8610.18271410.15282872X-RAY DIFFRACTION100
2.861-2.99110.1971350.1562845X-RAY DIFFRACTION100
2.9911-3.14870.16021490.14032847X-RAY DIFFRACTION100
3.1487-3.34590.17711680.14942871X-RAY DIFFRACTION100
3.3459-3.6040.1671590.14182850X-RAY DIFFRACTION100
3.604-3.96640.13851540.1292849X-RAY DIFFRACTION100
3.9664-4.53940.13991420.12322868X-RAY DIFFRACTION100
4.5394-5.71580.13591490.12832890X-RAY DIFFRACTION100
5.7158-36.98780.15191530.15552907X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 13.491 Å / Origin y: 0.2141 Å / Origin z: 22.5647 Å
111213212223313233
T0.0397 Å2-0.0031 Å2-0.0069 Å2-0.0644 Å2-0.0066 Å2--0.0659 Å2
L0.2033 °20.0526 °2-0.0656 °2-0.3938 °2-0.1261 °2--0.3565 °2
S0.0203 Å °-0.0151 Å °-0.0001 Å °-0.0256 Å °-0.0076 Å °-0.0223 Å °-0.0044 Å °0.0485 Å °-0.0128 Å °
Refinement TLS groupSelection details: ALL

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