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- PDB-6peb: Crystal Structure of human NAMPT in complex with NVP-LTM976 -

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Basic information

Entry
Database: PDB / ID: 6peb
TitleCrystal Structure of human NAMPT in complex with NVP-LTM976
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-OE4 / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.46 Å
AuthorsWeihofen, W.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Scaffold Morphing Identifies 3-Pyridyl Azetidine Ureas as Inhibitors of Nicotinamide Phosphoribosyltransferase (NAMPT).
Authors: Palacios, D.S. / Meredith, E.L. / Kawanami, T. / Adams, C.M. / Chen, X. / Darsigny, V. / Palermo, M. / Baird, D. / George, E.L. / Guy, C. / Hewett, J. / Tierney, L. / Thigale, S. / Wang, L. / Weihofen, W.A.
History
DepositionJun 20, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 11, 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)229,62219
Polymers227,2454
Non-polymers2,37715
Water10,539585
1
A: Nicotinamide phosphoribosyltransferase
B: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,01710
Polymers113,6222
Non-polymers1,3958
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Nicotinamide phosphoribosyltransferase
D: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,6059
Polymers113,6222
Non-polymers9827
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.740, 96.160, 246.840
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: 56811.180 Da / Num. of mol.: 4
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-OE4 / N-{4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-(pyridin-3-yl)azetidine-1-carboxamide


Mass: 412.441 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C24H20N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 585 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.34 Å3/Da / Density % sol: 47.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.8
Details: 100 mM NaPO4, pH 8.8 34 % (w/v) PEG 3350 180 mM NaCl. Equal volumes (0.5 uL) of reservoir solution and protein. Compound was soaked overnight at 1 mM concentration in crystallization solution.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.46→246.84 Å / Num. obs: 78824 / % possible obs: 99.9 % / Observed criterion σ(I): 3.3 / Redundancy: 6.5 % / Biso Wilson estimate: 64.31 Å2 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.039 / Rrim(I) all: 0.073 / Rsym value: 0.061 / Net I/σ(I): 17.9
Reflection shellResolution: 2.46→2.59 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 3.3 / Num. unique obs: 2145 / Rpim(I) all: 0.215 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
XSCALEdata scaling
BUSTER-TNTphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6ATB
Resolution: 2.46→34.94 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.399 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.428 / SU Rfree Blow DPI: 0.23 / SU Rfree Cruickshank DPI: 0.231
RfactorNum. reflection% reflectionSelection details
Rfree0.209 3962 5.03 %RANDOM
Rwork0.159 ---
obs0.161 78711 99.9 %-
Displacement parametersBiso mean: 72.66 Å2
Baniso -1Baniso -2Baniso -3
1-1.7997 Å20 Å20 Å2
2---15.5129 Å20 Å2
3---13.7132 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: 1 / Resolution: 2.46→34.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15019 0 153 706 15878
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0115524HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1421044HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5348SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes2579HARMONIC5
X-RAY DIFFRACTIONt_it15524HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.07
X-RAY DIFFRACTIONt_other_torsion19.56
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1966SEMIHARMONIC5
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_contact18575SEMIHARMONIC4
LS refinement shellResolution: 2.46→2.47 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.326 -5.46 %
Rwork0.2041 1489 -
all0.2103 1575 -
obs--99.93 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
11.28540.2086-0.35090.7371-0.01631.9039-0.02170.0087-0.09720.1391-0.04990.09090.3634-0.2970.0716-0.0676-0.01520.0177-0.1387-0.0274-0.117722.8513.96793.7132
21.57890.2968-0.57870.8081-0.08811.68840.013-0.3891-0.18560.3142-0.0938-0.11010.40610.19750.08080.05510.0163-0.0349-0.14660.0686-0.176136.7148-2.877820.1019
31.05430.67571.11741.03970.6981.5159-0.21350.4914-0.0096-0.07330.427-0.1918-0.24240.5757-0.2136-0.1988-0.10030.05180.1946-0.1764-0.142915.824249.117138.8766
42.12350.7658-0.09121.31990.7781.6652-0.0930.1169-0.35480.2770.461-0.52990.16880.6576-0.3681-0.25230.1012-0.08780.1702-0.304-0.114525.047336.264755.5528
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }

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