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- PDB-6atb: Crystal Structure of human NAMPT in complex with NVP-LOD812 -

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Basic information

Entry
Database: PDB / ID: 6atb
TitleCrystal Structure of human NAMPT in complex with NVP-LOD812
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTRANSFERASE / Complex
Function / homology
Function and homology information


nicotinamide phosphoribosyltransferase / nicotinamide phosphoribosyltransferase activity / : / 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 ...nicotinamide phosphoribosyltransferase / nicotinamide phosphoribosyltransferase activity / : / 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 ERK1 and ERK2 cascade / positive regulation of canonical NF-kappaB signal transduction / 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 phosphoribosyltransferase, N-terminal domain / Nicotinamide phosphoribosyltransferase, N-terminal domain / Nicotinamide phosphoribosyl transferase / 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-BWA / PHOSPHATE ION / 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
DepositionAug 28, 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

Downloads & links

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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)230,23418
Polymers227,7704
Non-polymers2,46414
Water20,2311123
1
A: Nicotinamide phosphoribosyltransferase
B: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,0328
Polymers113,8852
Non-polymers1,1476
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9340 Å2
ΔGint-55 kcal/mol
Surface area32340 Å2
MethodPISA
2
C: Nicotinamide phosphoribosyltransferase
D: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,20210
Polymers113,8852
Non-polymers1,3178
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10130 Å2
ΔGint-52 kcal/mol
Surface area31790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)98.460, 208.400, 98.860
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 4 molecules ABCD

#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 (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P43490, nicotinamide phosphoribosyltransferase

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Non-polymers , 5 types, 1137 molecules

#2: Chemical
ChemComp-BWA / N-{4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-N'-[(pyridin-3-yl)methyl]urea


Mass: 386.403 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H18N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1123 / 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: 2.23 Å3/Da / Density % sol: 44.76 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 18 % (v/v) glycerol 23 % (w/v) PEG 3350 200 mM NaCl 100 mM Tris/HCl pH 8.0
Temp details: Crystallization SETUP AND INCUBATION AT ROOM TEMPERATURE.

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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: Feb 14, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.53→207.99 Å / Num. obs: 77346 / % possible obs: 99.8 % / Redundancy: 6 % / Biso Wilson estimate: 44.89 Å2 / Rmerge(I) obs: 0.142 / Net I/av σ(I): 6.6 / Net I/σ(I): 8.6
Reflection shellResolution: 2.53→2.67 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.476 / Mean I/σ(I) obs: 3.2 / % possible all: 99.9

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Processing

Software
NameVersionClassification
XDSdata reduction
SCALAdata scaling
BUSTERphasing
BUSTER2.11.2refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3DGR

3dgr


Resolution: 2.53→104.2 Å / Cor.coef. Fo:Fc: 0.9472 / Cor.coef. Fo:Fc free: 0.9093 / SU R Cruickshank DPI: 0.425 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.504 / SU Rfree Blow DPI: 0.241 / SU Rfree Cruickshank DPI: 0.239
RfactorNum. reflection% reflectionSelection details
Rfree0.2147 3492 5.03 %RANDOM
Rwork0.1523 ---
obs0.1555 77346 99.96 %-
Displacement parametersBiso mean: 39.24 Å2
Baniso -1Baniso -2Baniso -3
1-7.3066 Å20 Å20 Å2
2---9.9568 Å20 Å2
3---2.6502 Å2
Refine analyzeLuzzati coordinate error obs: 0.218 Å
Refinement stepCycle: LAST / Resolution: 2.53→104.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14966 0 1293 1123 17382
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0115490HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1620980HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5346SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes391HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2182HARMONIC5
X-RAY DIFFRACTIONt_it15490HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.13
X-RAY DIFFRACTIONt_other_torsion18.92
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1958SEMIHARMONIC5
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_contact19129SEMIHARMONIC4
LS refinement shellResolution: 2.53→2.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2624 293 5.19 %
Rwork0.178 5354 -
all0.1827 5647 -
obs--99.96 %

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