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- PDB-6b76: Crystal Structure of human NAMPT in complex with NVP-LVR596 -

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Basic information

Entry
Database: PDB / ID: 6b76
TitleCrystal Structure of human NAMPT in complex with NVP-LVR596
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTRANSFERASE
Function / homology
Function and homology information


nicotinamide phosphoribosyltransferase / nicotinamide phosphoribosyltransferase activity / : / Nicotinamide salvage / NAD+ biosynthetic process / NPAS4 regulates expression of target genes / BMAL1:CLOCK,NPAS2 activates circadian expression / cytokine activity / circadian regulation of gene expression / cell junction ...nicotinamide phosphoribosyltransferase / nicotinamide phosphoribosyltransferase activity / : / Nicotinamide salvage / NAD+ biosynthetic process / NPAS4 regulates expression of target genes / BMAL1:CLOCK,NPAS2 activates circadian expression / cytokine activity / circadian regulation of gene expression / cell junction / cell-cell signaling / positive regulation of canonical NF-kappaB signal transduction / positive regulation of ERK1 and ERK2 cascade / nuclear speck / inflammatory response / positive regulation of cell population proliferation / positive regulation of gene expression / 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-CVJ / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.44 Å
AuthorsWeihofen, W.A. / Thigale, S.
CitationJournal: To Be Published
Title: Identification and structure based design of cellularly active cyclo-propyl carboxamide Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors
Authors: Palacios, D. / Meredith, E. / Kawanami, T. / Adams, C. / Chen, X. / Darsigny, V. / Geno, E. / Palermo, M. / Guy, C. / Hewett, J. / Tierney, L. / THigale, S. / Weihofen, W.A. / Agrikar, U. / ...Authors: Palacios, D. / Meredith, E. / Kawanami, T. / Adams, C. / Chen, X. / Darsigny, V. / Geno, E. / Palermo, M. / Guy, C. / Hewett, J. / Tierney, L. / THigale, S. / Weihofen, W.A. / Agrikar, U. / Boynton, G. / George, E. / Wang, L.
History
DepositionOct 3, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 3, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Nicotinamide phosphoribosyltransferase
B: Nicotinamide phosphoribosyltransferase
C: Nicotinamide phosphoribosyltransferase
D: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)230,16419
Polymers227,7704
Non-polymers2,39415
Water15,745874
1
A: Nicotinamide phosphoribosyltransferase
B: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,12910
Polymers113,8852
Non-polymers1,2458
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10350 Å2
ΔGint-82 kcal/mol
Surface area32370 Å2
MethodPISA
2
C: Nicotinamide phosphoribosyltransferase
D: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,0349
Polymers113,8852
Non-polymers1,1507
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10050 Å2
ΔGint-71 kcal/mol
Surface area32600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.870, 96.830, 248.300
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 56942.375 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NAMPT, PBEF, PBEF1 / Plasmid: pET41 / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: P43490, nicotinamide phosphoribosyltransferase
#2: Chemical
ChemComp-CVJ / (1S,2S)-N-{4-[(1S)-1-(propanoylamino)ethyl]phenyl}-2-(pyridin-3-yl)cyclopropane-1-carboxamide


Mass: 337.416 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H23N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 874 / 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: 48.14 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 25 % (w/v) PEG 3350, 200 mM NaCl, 100 mM Tris/HCl pH 8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 3, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.44→248.3 Å / Num. obs: 81287 / % possible obs: 100 % / Redundancy: 6.6 % / Biso Wilson estimate: 61.26 Å2 / Rmerge(I) obs: 0.065 / Net I/σ(I): 18.4
Reflection shellResolution: 2.44→2.57 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.582 / Mean I/σ(I) obs: 2.6 / Num. unique all: 11185 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSdata reduction
SCALAdata scaling
BUSTER2.11.4refinement
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6atb

6atb


Resolution: 2.44→124.15 Å / Cor.coef. Fo:Fc: 0.9363 / Cor.coef. Fo:Fc free: 0.9175 / SU R Cruickshank DPI: 0.424 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.457 / SU Rfree Blow DPI: 0.252 / SU Rfree Cruickshank DPI: 0.252
RfactorNum. reflection% reflectionSelection details
Rfree0.2327 4070 5.01 %RANDOM
Rwork0.1787 ---
obs0.1814 81198 99.68 %-
Displacement parametersBiso mean: 58.39 Å2
Baniso -1Baniso -2Baniso -3
1-3.3529 Å20 Å20 Å2
2---15.3302 Å20 Å2
3---11.9774 Å2
Refine analyzeLuzzati coordinate error obs: 0.284 Å
Refinement stepCycle: LAST / Resolution: 2.44→124.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15028 0 1031 876 16935
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0115532HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1521048HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5366SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes395HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2190HARMONIC5
X-RAY DIFFRACTIONt_it15532HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.01
X-RAY DIFFRACTIONt_other_torsion19.47
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1979SEMIHARMONIC5
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_contact18770SEMIHARMONIC4
LS refinement shellResolution: 2.44→2.5 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3015 331 5.82 %
Rwork0.2237 5359 -
all0.228 5690 -
obs--99.68 %

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