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- PDB-4o28: Structural Basis for Resistance to Diverse Classes of NAMPT Inhibitors -

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Basic information

Entry
Database: PDB / ID: 4o28
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+ 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-1QS / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 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 17, 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
B: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,04721
Polymers114,0052
Non-polymers2,04219
Water14,304794
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12570 Å2
ΔGint-19 kcal/mol
Surface area32710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.327, 106.208, 83.651
Angle α, β, γ (deg.)90.00, 96.71, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 2 / 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-1QS / N-{4-[(3,5-difluorophenyl)sulfonyl]benzyl}imidazo[1,2-a]pyridine-6-carboxamide


Mass: 427.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H15F2N3O3S
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


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


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


Mass: 18.015 Da / Num. of mol.: 794 / 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: 2.33 Å3/Da / Density % sol: 47.31 %

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.97397 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 16, 2013
RadiationMonochromator: Liquid Nitrogen cooled Dual Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97397 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 71575 / Num. obs: 71575 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 2→2.07 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: 2→46.365 Å / SU ML: 0.23 / σ(F): 1.35 / Phase error: 18.51 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1938 3621 5.06 %
Rwork0.1497 --
obs0.152 71528 98.58 %
all-71575 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 33.57 Å2 / ksol: 0.373 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-13.2696 Å20 Å20.615 Å2
2--8.0794 Å20 Å2
3---4.0873 Å2
Refinement stepCycle: LAST / Resolution: 2→46.365 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7464 0 132 794 8390
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077770
X-RAY DIFFRACTIONf_angle_d1.05610507
X-RAY DIFFRACTIONf_dihedral_angle_d12.5872844
X-RAY DIFFRACTIONf_chiral_restr0.0721137
X-RAY DIFFRACTIONf_plane_restr0.0051327
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.00840.2839840.21461723X-RAY DIFFRACTION64
2.0084-2.03590.24111440.19182627X-RAY DIFFRACTION100
2.0359-2.0650.23491430.1732610X-RAY DIFFRACTION100
2.065-2.09580.24191530.16832636X-RAY DIFFRACTION100
2.0958-2.12850.22311510.15592606X-RAY DIFFRACTION100
2.1285-2.16340.21311440.15152663X-RAY DIFFRACTION100
2.1634-2.20070.20851650.14932588X-RAY DIFFRACTION100
2.2007-2.24070.20411550.14752642X-RAY DIFFRACTION100
2.2407-2.28380.18571410.13952639X-RAY DIFFRACTION100
2.2838-2.33050.21661520.14862650X-RAY DIFFRACTION100
2.3305-2.38110.22151470.14892599X-RAY DIFFRACTION100
2.3811-2.43650.23971240.1542684X-RAY DIFFRACTION100
2.4365-2.49740.19891370.1442642X-RAY DIFFRACTION100
2.4974-2.5650.21071240.14922655X-RAY DIFFRACTION100
2.565-2.64040.18741260.1442654X-RAY DIFFRACTION100
2.6404-2.72570.1981460.15072677X-RAY DIFFRACTION100
2.7257-2.82310.21481370.1592620X-RAY DIFFRACTION100
2.8231-2.93610.21411280.1672658X-RAY DIFFRACTION100
2.9361-3.06970.20921420.15822649X-RAY DIFFRACTION100
3.0697-3.23150.21751400.14992671X-RAY DIFFRACTION100
3.2315-3.43390.17551450.15442629X-RAY DIFFRACTION100
3.4339-3.69890.19621430.14662659X-RAY DIFFRACTION100
3.6989-4.07090.16481380.13042680X-RAY DIFFRACTION100
4.0709-4.65950.14251530.12052649X-RAY DIFFRACTION100
4.6595-5.86870.15511220.13972680X-RAY DIFFRACTION100
5.8687-46.37740.17461370.16752717X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 13.3849 Å / Origin y: 1.655 Å / Origin z: 22.873 Å
111213212223313233
T-0.0089 Å20.0005 Å2-0.0055 Å2--0.0026 Å20.0133 Å2---0.0158 Å2
L0.0377 °2-0.001 °2-0.0082 °2-0.0373 °20.0112 °2--0.0433 °2
S0.0196 Å °-0.0134 Å °-0.0025 Å °-0.0405 Å °0.0273 Å °-0.026 Å °0.0006 Å °0.0429 Å °0.0615 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:487 OR RESID 603:608 ) ) OR ( CHAIN B AND ( RESID 8:487 OR RESID 603:611 ) )A8 - 487
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:487 OR RESID 603:608 ) ) OR ( CHAIN B AND ( RESID 8:487 OR RESID 603:611 ) )A603 - 608
3X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:487 OR RESID 603:608 ) ) OR ( CHAIN B AND ( RESID 8:487 OR RESID 603:611 ) )B8 - 487
4X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:487 OR RESID 603:608 ) ) OR ( CHAIN B AND ( RESID 8:487 OR RESID 603:611 ) )B603 - 611

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