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- PDB-6b75: Crystal Structure of human NAMPT in complex with NVP-LOQ594 -

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Basic information

Entry
Database: PDB / ID: 6b75
TitleCrystal Structure of human NAMPT in complex with NVP-LOQ594
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-CVP / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / 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
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)229,1457
Polymers227,7704
Non-polymers1,3763
Water12,340685
1
A: Nicotinamide phosphoribosyltransferase
B: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,8024
Polymers113,8852
Non-polymers9172
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8350 Å2
ΔGint-44 kcal/mol
Surface area32390 Å2
MethodPISA
2
C: Nicotinamide phosphoribosyltransferase
D: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,3433
Polymers113,8852
Non-polymers4591
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8490 Å2
ΔGint-42 kcal/mol
Surface area32500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.049, 207.985, 98.466
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 / Production host: Escherichia coli (E. coli)
References: UniProt: P43490, nicotinamide phosphoribosyltransferase
#2: Chemical ChemComp-CVP / 4-[(piperazin-1-yl)methyl]-N-{[4-({[(pyridin-3-yl)methyl]carbamoyl}amino)phenyl]methyl}benzamide


Mass: 458.555 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C26H30N6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 685 / 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: 2.2 Å3/Da / Density % sol: 44.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 100 mM Tris/HCl pH 8.0, 23 % (w/v) PEG 3350, 200 mM NaCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Feb 14, 2014
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 % / Redundancy: 6 % / Biso Wilson estimate: 51.95 Å2 / Net I/σ(I): 8.6
Reflection shellResolution: 2.53→2.67 Å / Redundancy: 5.9 % / Mean I/σ(I) obs: 3.2 / Rsym value: 0.476 / % possible all: 99.9

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
XSCALEdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6atb

6atb


Resolution: 2.53→89 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.884 / SU R Cruickshank DPI: 0.854 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.051 / SU Rfree Blow DPI: 0.301 / SU Rfree Cruickshank DPI: 0.303
RfactorNum. reflection% reflectionSelection details
Rfree0.247 3404 5.06 %RANDOM
Rwork0.177 ---
obs0.181 67245 99 %-
Displacement parametersBiso mean: 40.78 Å2
Baniso -1Baniso -2Baniso -3
1-1.3338 Å20 Å20 Å2
2---2.674 Å20 Å2
3---1.3402 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: 1 / Resolution: 2.53→89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14923 0 102 685 15710
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0115403HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1520867HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5334SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes389HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2182HARMONIC5
X-RAY DIFFRACTIONt_it15403HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.11
X-RAY DIFFRACTIONt_other_torsion19.02
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1956SEMIHARMONIC5
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_contact19109SEMIHARMONIC4
LS refinement shellResolution: 2.53→2.6 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2766 214 4.66 %
Rwork0.2025 4380 -
all0.206 4594 -
obs--93.4 %

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