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- PDB-4o16: Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors -

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Basic information

Entry
Database: PDB / ID: 4o16
TitleStructural Basis for Resistance to Diverse Classes of NAMPT Inhibitors
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex
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-1XC / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.783 Å
AuthorsOh, A. / Coons, M. / Brillantes, B. / Wang, W.
CitationJournal: Plos One / Year: 2014
Title: Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors.
Authors: Wang, W. / Elkins, K. / Oh, A. / Ho, Y.C. / Wu, J. / Li, H. / Xiao, Y. / Kwong, M. / Coons, M. / Brillantes, B. / Cheng, E. / Crocker, L. / Dragovich, P.S. / Sampath, D. / Zheng, X. / Bair, ...Authors: Wang, W. / Elkins, K. / Oh, A. / Ho, Y.C. / Wu, J. / Li, H. / Xiao, Y. / Kwong, M. / Coons, M. / Brillantes, B. / Cheng, E. / Crocker, L. / Dragovich, P.S. / Sampath, D. / Zheng, X. / Bair, K.W. / O'Brien, T. / Belmont, L.D.
History
DepositionDec 15, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 22, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,64017
Polymers57,0021
Non-polymers1,63716
Water4,504250
1
A: Nicotinamide phosphoribosyltransferase
hetero molecules

A: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,28034
Polymers114,0052
Non-polymers3,27532
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area14500 Å2
ΔGint2 kcal/mol
Surface area32520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.671, 107.360, 52.780
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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


Mass: 57002.477 Da / Num. of mol.: 1 / Mutation: S165F
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-1XC / 6-({4-[(3,5-difluorophenyl)sulfonyl]benzyl}carbamoyl)-1-(5-O-phosphono-beta-D-ribofuranosyl)imidazo[1,2-a]pyridin-1-ium


Mass: 640.526 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H25F2N3O10PS
#3: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 250 / 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: 2.1 Å3/Da / Density % sol: 41.55 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 8.6
Details: 0.1M Sodium phosphate, pH 8.6, 25% polyethylene glycol 3350, 0.2M NaCl and 1mM compound, followed by in-situ adduct formation, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 15, 2013
RadiationMonochromator: Liquid Nitrogen cooled Dual Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.78→50 Å / Num. all: 46649 / Num. obs: 46649 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 1.78→1.84 Å / % possible all: 100

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Processing

Software
NameVersionClassification
B3data collection
PHASERphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.783→47.366 Å / SU ML: 0.23 / σ(F): 1.34 / Phase error: 21.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.219 2324 4.99 %
Rwork0.1779 --
all0.219 46649 -
obs0.1799 46597 99.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 35.861 Å2 / ksol: 0.357 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-11.0863 Å20 Å20 Å2
2--1.8961 Å20 Å2
3---12.4126 Å2
Refinement stepCycle: LAST / Resolution: 1.783→47.366 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3765 0 105 250 4120
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.013948
X-RAY DIFFRACTIONf_angle_d1.25330
X-RAY DIFFRACTIONf_dihedral_angle_d13.0721444
X-RAY DIFFRACTIONf_chiral_restr0.084577
X-RAY DIFFRACTIONf_plane_restr0.006672
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.783-1.81910.32731380.28742501X-RAY DIFFRACTION97
1.8191-1.85870.27941340.24572551X-RAY DIFFRACTION100
1.8587-1.90190.25621350.22822574X-RAY DIFFRACTION100
1.9019-1.94950.28561520.22342566X-RAY DIFFRACTION100
1.9495-2.00220.24591360.19862546X-RAY DIFFRACTION100
2.0022-2.06110.2631380.19872599X-RAY DIFFRACTION100
2.0611-2.12760.221170.18682601X-RAY DIFFRACTION100
2.1276-2.20370.22511340.17442591X-RAY DIFFRACTION100
2.2037-2.29190.19841390.17632590X-RAY DIFFRACTION100
2.2919-2.39620.21891310.1722594X-RAY DIFFRACTION100
2.3962-2.52250.22721340.17692594X-RAY DIFFRACTION100
2.5225-2.68060.27291330.18742600X-RAY DIFFRACTION100
2.6806-2.88750.26191220.19382620X-RAY DIFFRACTION100
2.8875-3.1780.22291440.1832629X-RAY DIFFRACTION100
3.178-3.63780.17911560.1622624X-RAY DIFFRACTION100
3.6378-4.58260.18761340.14822687X-RAY DIFFRACTION100
4.5826-47.38230.20121470.16912806X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -8.857 Å / Origin y: -7.4075 Å / Origin z: 10.7921 Å
111213212223313233
T0.0004 Å20.0036 Å2-0.0611 Å2-0.0342 Å2-0.0188 Å2--0.0194 Å2
L0.097 °20.0911 °2-0.0103 °2-0.1995 °2-0.0858 °2--0.1646 °2
S-0.0903 Å °0.0246 Å °-0.0057 Å °-0.2297 Å °-0.0008 Å °0.0474 Å °0.0843 Å °-0.043 Å °-0.1419 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:487 OR RESID 605:616 ) )A8 - 487
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:487 OR RESID 605:616 ) )A605 - 616

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