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- PDB-6azj: Crystal Structure of human NAMPT in complex with NVP-LQN520 -

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Basic information

Entry
Database: PDB / ID: 6azj
TitleCrystal Structure of human NAMPT in complex with NVP-LQN520
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTRANSFERASE
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-C5V / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.53 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
DepositionSep 11, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 12, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,2564
Polymers112,4612
Non-polymers7952
Water5,242291
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7450 Å2
ΔGint-41 kcal/mol
Surface area33330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.230, 157.720, 192.180
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-733-

HOH

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Components

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


Mass: 56230.551 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NAMPT, PBEF, PBEF1 / Plasmid: pET47b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P43490, nicotinamide phosphoribosyltransferase
#2: Chemical ChemComp-C5V / (1S,2S)-N-{4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-(pyridin-3-yl)cyclopropane-1-carboxamide


Mass: 397.426 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H19N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 291 / 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: 2.06 Å3/Da / Density % sol: 40.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 100 mM Hepes pH 6.5, 30-36 % Jeffamine ED-2001

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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: 2.53→208 Å / Num. obs: 67507 / % possible obs: 99.8 % / Observed criterion σ(F): 2 / Redundancy: 6 % / Biso Wilson estimate: 49.63 Å2 / Rmerge(I) obs: 0.142 / Rpim(I) all: 0.094 / Net I/σ(I): 8.6
Reflection shellResolution: 2.53→2.65 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.476 / Mean I/σ(I) obs: 3.2 / Num. unique obs: 9745 / Rpim(I) all: 0.322 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
XSCALEdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2e5b

2e5b


Resolution: 2.53→96.09 Å / Cor.coef. Fo:Fc: 0.9376 / Cor.coef. Fo:Fc free: 0.8994 / SU R Cruickshank DPI: 0.504 / Cross valid method: THROUGHOUT / σ(F): 2 / SU R Blow DPI: 0.535 / SU Rfree Blow DPI: 0.253 / SU Rfree Cruickshank DPI: 0.255
RfactorNum. reflection% reflectionSelection details
Rfree0.2288 1566 5 %RANDOM
Rwork0.1706 ---
obs0.1735 36420 99.93 %-
Displacement parametersBiso mean: 50.08 Å2
Baniso -1Baniso -2Baniso -3
1-8.2361 Å20 Å20 Å2
2--3.174 Å20 Å2
3----11.4101 Å2
Refine analyzeLuzzati coordinate error obs: 0.261 Å
Refinement stepCycle: 1 / Resolution: 2.53→96.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7439 0 60 291 7790
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.017681HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1810409HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2650SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes194HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1084HARMONIC5
X-RAY DIFFRACTIONt_it7681HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.94
X-RAY DIFFRACTIONt_other_torsion20.54
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion977SEMIHARMONIC5
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_contact9242SEMIHARMONIC4
LS refinement shellResolution: 2.53→2.58 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.3379 150 5.12 %
Rwork0.2079 2780 -
all0.2145 2930 -
obs--99.93 %

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