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- PDB-4lvb: Fragment-based Identification of Amides Derived From trans-2-(Pyr... -

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Basic information

Entry
Database: PDB / ID: 4lvb
TitleFragment-based Identification of Amides Derived From trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


nicotinamide phosphoribosyltransferase activity / nicotinamide phosphoribosyltransferase / NAD biosynthesis via nicotinamide riboside salvage pathway / Nicotinamide salvaging / NAD biosynthetic process / : / NPAS4 regulates expression of target genes / BMAL1:CLOCK,NPAS2 activates circadian gene expression / cytokine activity / circadian regulation of gene expression ...nicotinamide phosphoribosyltransferase activity / nicotinamide phosphoribosyltransferase / NAD biosynthesis via nicotinamide riboside salvage pathway / Nicotinamide salvaging / NAD 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
N-[4-(acetylamino)phenyl]cyclopropanecarboxamide / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.836 Å
AuthorsGiannetti, A.M. / Zheng, X. / Skelton, N. / Wang, W. / Bravo, B. / Feng, Y. / Gunzner-Toste, J. / Ho, Y. / Hua, R. / Wang, C. ...Giannetti, A.M. / Zheng, X. / Skelton, N. / Wang, W. / Bravo, B. / Feng, Y. / Gunzner-Toste, J. / Ho, Y. / Hua, R. / Wang, C. / Zhao, Q. / Liederer, B.M. / Liu, Y. / O'Brien, T. / Oeh, J. / Sampath, D. / Shen, Y. / Wang, L. / Wu, H. / Xiao, Y. / Yuen, P. / Zak, M. / Zhao, G. / Dragovich, P.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
Authors: Zheng, X. / Bair, K.W. / Bauer, P. / Baumeister, T. / Bowman, K.K. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Feng, Y. / Han, B. / Ho, Y.C. / Kley, N. / Li, H. / Liang, X. / ...Authors: Zheng, X. / Bair, K.W. / Bauer, P. / Baumeister, T. / Bowman, K.K. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Feng, Y. / Han, B. / Ho, Y.C. / Kley, N. / Li, H. / Liang, X. / Liederer, B.M. / Lin, J. / Ly, J. / O'Brien, T. / Oeh, J. / Oh, A. / Reynolds, D.J. / Sampath, D. / Sharma, G. / Skelton, N. / Smith, C.C. / Tremayne, J. / Wang, L. / Wang, W. / Wang, Z. / Wu, H. / Wu, J. / Xiao, Y. / Yang, G. / Yuen, P.W. / Zak, M. / Dragovich, P.S.
History
DepositionJul 26, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2013Group: Database references
Revision 1.2Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Feb 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)114,6979
Polymers113,8852
Non-polymers8137
Water17,402966
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9530 Å2
ΔGint-41 kcal/mol
Surface area33220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.612, 106.681, 83.142
Angle α, β, γ (deg.)90.00, 96.39, 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: 56942.375 Da / Num. of mol.: 2
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-20N / N-[4-(acetylamino)phenyl]cyclopropanecarboxamide


Mass: 218.252 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H14N2O2
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


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


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 966 / 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: 2.35 Å3/Da / Density % sol: 47.56 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.6
Details: 0.2uL + 0.2uL drops containing 6mg/mL Nampt, 0.1M Sodium phosphate, 25-29% polyethylene glycol 3350, 0.2M NaCl, pH 8.6, VAPOR DIFFUSION, HANGING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.97945 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 25, 2012
RadiationMonochromator: Double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97945 Å / Relative weight: 1
ReflectionResolution: 1.836→82.63 Å / Num. all: 91599 / Num. obs: 90042 / % possible obs: 98.3 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 1.836→1.846 Å / % possible all: 98.4

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.836→82.63 Å / SU ML: 0.26 / σ(F): 1.2 / Phase error: 22.05 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2154 4300 5 %5% random
Rwork0.1752 ---
all0.2154 91599 --
obs0.1772 89996 95.09 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 29.151 Å2 / ksol: 0.344 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-15.7742 Å20 Å2-2.3029 Å2
2--8.3911 Å20 Å2
3---3.9467 Å2
Refinement stepCycle: LAST / Resolution: 1.836→82.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7524 0 54 966 8544
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077751
X-RAY DIFFRACTIONf_angle_d1.03910495
X-RAY DIFFRACTIONf_dihedral_angle_d12.3132852
X-RAY DIFFRACTIONf_chiral_restr0.0721148
X-RAY DIFFRACTIONf_plane_restr0.0051333
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.836-1.85640.31512960.29075525X-RAY DIFFRACTION97
1.8564-1.87820.31442640.28175582X-RAY DIFFRACTION97
1.8782-1.90110.31372640.26545600X-RAY DIFFRACTION97
1.9011-1.92520.3212780.26055445X-RAY DIFFRACTION97
1.9252-1.95050.28692860.23585622X-RAY DIFFRACTION97
1.9505-1.97720.30232760.24385536X-RAY DIFFRACTION96
1.9772-2.00550.27882940.2335439X-RAY DIFFRACTION96
2.0055-2.03540.27393180.21765515X-RAY DIFFRACTION96
2.0354-2.06720.27283090.20755433X-RAY DIFFRACTION96
2.0672-2.10110.223050.19665447X-RAY DIFFRACTION95
2.1011-2.13740.28633040.20075417X-RAY DIFFRACTION95
2.1374-2.17620.27593000.2065293X-RAY DIFFRACTION92
2.1762-2.21810.2422590.19375420X-RAY DIFFRACTION94
2.2181-2.26340.23332620.17675550X-RAY DIFFRACTION96
2.2634-2.31260.25872830.17585561X-RAY DIFFRACTION96
2.3126-2.36640.24773050.18375486X-RAY DIFFRACTION96
2.3664-2.42560.24052530.16915509X-RAY DIFFRACTION96
2.4256-2.49110.21573050.16475506X-RAY DIFFRACTION96
2.4911-2.56450.24082830.17225462X-RAY DIFFRACTION96
2.5645-2.64720.20533280.16085435X-RAY DIFFRACTION95
2.6472-2.74190.20583010.16315337X-RAY DIFFRACTION93
2.7419-2.85160.21912880.16545232X-RAY DIFFRACTION91
2.8516-2.98140.2182670.1725512X-RAY DIFFRACTION96
2.9814-3.13860.20492810.15935487X-RAY DIFFRACTION95
3.1386-3.33530.19112710.16995351X-RAY DIFFRACTION94
3.3353-3.59280.18982840.16375467X-RAY DIFFRACTION94
3.5928-3.95430.17042710.14365251X-RAY DIFFRACTION92
3.9543-4.52650.15692770.13145213X-RAY DIFFRACTION91
4.5265-5.70270.15713120.13475379X-RAY DIFFRACTION94
5.7027-82.630.18362770.17575412X-RAY DIFFRACTION94
Refinement TLS params.Method: refined / Origin x: 13.5738 Å / Origin y: 1.4741 Å / Origin z: 22.7455 Å
111213212223313233
T-0.0357 Å2-0.004 Å20.0045 Å2--0.0041 Å20.0188 Å2---0.0261 Å2
L0.0405 °2-0.0029 °2-0.0004 °2-0.0704 °2-0.0007 °2--0.0375 °2
S0.0393 Å °-0.0054 Å °-0.0061 Å °-0.065 Å °0.0148 Å °-0.008 Å °0.0103 Å °0.0453 Å °0.0816 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:487 OR RESID 603:603 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:604 ) )A8 - 487
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:487 OR RESID 603:603 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:604 ) )A603
3X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:487 OR RESID 603:603 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:604 ) )B8 - 486
4X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:487 OR RESID 603:603 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:604 ) )B603 - 604

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