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- PDB-5upe: Crystal structure of human NAMPT with isoindoline urea inhibitor ... -

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Basic information

Entry
Database: PDB / ID: 5upe
TitleCrystal structure of human NAMPT with isoindoline urea inhibitor compound 5
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / NAMPT 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-8HY / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 Å
AuthorsLongenecker, K.L. / Raich, D. / Korepanova, A.V.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).
Authors: Curtin, M.L. / Heyman, H.R. / Clark, R.F. / Sorensen, B.K. / Doherty, G.A. / Hansen, T.M. / Frey, R.R. / Sarris, K.A. / Aguirre, A.L. / Shrestha, A. / Tu, N. / Woller, K. / Pliushchev, M.A. ...Authors: Curtin, M.L. / Heyman, H.R. / Clark, R.F. / Sorensen, B.K. / Doherty, G.A. / Hansen, T.M. / Frey, R.R. / Sarris, K.A. / Aguirre, A.L. / Shrestha, A. / Tu, N. / Woller, K. / Pliushchev, M.A. / Sweis, R.F. / Cheng, M. / Wilsbacher, J.L. / Kovar, P.J. / Guo, J. / Cheng, D. / Longenecker, K.L. / Raich, D. / Korepanova, A.V. / Soni, N.B. / Algire, M.A. / Richardson, P.L. / Marin, V.L. / Badagnani, I. / Vasudevan, A. / Buchanan, F.G. / Maag, D. / Chiang, G.G. / Tse, C. / Michaelides, M.R.
History
DepositionFeb 2, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 19, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Mar 21, 2018Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.pdbx_collection_date
Revision 1.4Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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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)113,9794
Polymers113,1842
Non-polymers7952
Water11,115617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8350 Å2
ΔGint-43 kcal/mol
Surface area32410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.073, 106.448, 83.109
Angle α, β, γ (deg.)90.000, 96.630, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Nicotinamide phosphoribosyltransferase / / Nampt / Pre-B-cell colony-enhancing factor 1 / Pre-B cell-enhancing factor / Visfatin


Mass: 56591.898 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NAMPT, PBEF, PBEF1 / Cell line (production host): HEK 293-6E / Production host: Mammalia (mammals)
References: UniProt: P43490, nicotinamide phosphoribosyltransferase
#2: Chemical ChemComp-8HY / N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-2H-isoindole-2-carboxamide


Mass: 397.469 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H23N3O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 617 / 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: 2.37 Å3/Da / Density % sol: 48.12 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 25% PEG 3350, 0.2 M ammonium sulfate, and 0.1 M HEPES, pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.93→82.55 Å / Num. obs: 78276 / % possible obs: 99.3 % / Redundancy: 3.3 % / Biso Wilson estimate: 25.61 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.066 / Rrim(I) all: 0.122 / Rsym value: 0.102 / Net I/σ(I): 8.9
Reflection shellResolution: 1.933→1.94 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.865 / Mean I/σ(I) obs: 1.5 / CC1/2: 0.84 / Rpim(I) all: 0.417 / Rrim(I) all: 0.787 / Rsym value: 0.865 / % possible all: 97.7

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Processing

Software
NameVersionClassification
Aimlessdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
XDS(VERSION May 1)data reduction
autoPROCdata scaling
2016data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GVJ

2gvj


Resolution: 1.93→28.26 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.916 / SU R Cruickshank DPI: 0.153 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.154 / SU Rfree Blow DPI: 0.135 / SU Rfree Cruickshank DPI: 0.135
RfactorNum. reflection% reflectionSelection details
Rfree0.217 3923 5.03 %RANDOM
Rwork0.187 ---
obs0.189 78061 98.6 %-
Displacement parametersBiso max: 97.32 Å2 / Biso mean: 29.33 Å2 / Biso min: 11.52 Å2
Baniso -1Baniso -2Baniso -3
1--6.8449 Å20 Å2-3.5441 Å2
2---4.7656 Å20 Å2
3---11.6105 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: final / Resolution: 1.93→28.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7422 0 60 617 8099
Biso mean--29.53 38.85 -
Num. residues----928
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2666SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes194HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1124HARMONIC5
X-RAY DIFFRACTIONt_it7664HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion972SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact9460SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7664HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg10386HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion3.46
X-RAY DIFFRACTIONt_other_torsion17.16
LS refinement shellResolution: 1.93→1.98 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2437 263 4.82 %
Rwork0.213 5194 -
all0.2145 5457 -
obs--92.94 %

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