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

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Basic information

Entry
Database: PDB / ID: 4lva
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
Chem-20M / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 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)116,20922
Polymers113,8852
Non-polymers2,32420
Water18,1231006
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12670 Å2
ΔGint-40 kcal/mol
Surface area32060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.511, 106.799, 83.040
Angle α, β, γ (deg.)90.00, 96.59, 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-20M / N-(4-{[4-(pyrrolidin-1-yl)piperidin-1-yl]sulfonyl}benzyl)-2H-pyrido[4,3-e][1,2,4]thiadiazin-3-amine 1,1-dioxide


Mass: 504.626 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H28N6O4S2
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: PO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1006 / 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: 2.34 Å3/Da / Density % sol: 47.45 %
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, 1mM compound, pH 8.6, VAPOR DIFFUSION, HANGING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.97949 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Aug 30, 2012
RadiationMonochromator: Double Crystal Monochromator (ACCEL DCM) with an indirectly cryo-cooled first crystal and sagittally focusing second crystal
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.55→50 Å / Num. all: 151480 / Num. obs: 151480 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 1.55→1.61 Å / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.55→46.37 Å / SU ML: 0.17 / σ(F): 1.35 / Phase error: 20.9 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2069 7612 5.03 %
Rwork0.1765 --
obs0.178 151425 99.92 %
all-151480 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.55→46.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7519 0 146 1006 8671
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0157831
X-RAY DIFFRACTIONf_angle_d1.59610596
X-RAY DIFFRACTIONf_dihedral_angle_d13.7392868
X-RAY DIFFRACTIONf_chiral_restr0.1061147
X-RAY DIFFRACTIONf_plane_restr0.0091334
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.55-1.56750.27062790.24464676X-RAY DIFFRACTION99
1.5675-1.58590.29632350.23574774X-RAY DIFFRACTION100
1.5859-1.60530.26962540.22484771X-RAY DIFFRACTION100
1.6053-1.62560.2672500.22024765X-RAY DIFFRACTION100
1.6256-1.6470.25372610.21024812X-RAY DIFFRACTION100
1.647-1.66960.2532420.20494788X-RAY DIFFRACTION100
1.6696-1.69340.24212650.20164781X-RAY DIFFRACTION100
1.6934-1.71870.24362480.19434793X-RAY DIFFRACTION100
1.7187-1.74550.22242610.19014741X-RAY DIFFRACTION100
1.7455-1.77420.21922430.18174854X-RAY DIFFRACTION100
1.7742-1.80480.22522500.18124785X-RAY DIFFRACTION100
1.8048-1.83760.23232420.1764769X-RAY DIFFRACTION100
1.8376-1.87290.22322670.17854768X-RAY DIFFRACTION100
1.8729-1.91110.23542590.17754779X-RAY DIFFRACTION100
1.9111-1.95270.21222390.17154835X-RAY DIFFRACTION100
1.9527-1.99810.20632160.16794767X-RAY DIFFRACTION100
1.9981-2.04810.19682610.1664807X-RAY DIFFRACTION100
2.0481-2.10350.19892350.1694830X-RAY DIFFRACTION100
2.1035-2.16540.21062790.17034765X-RAY DIFFRACTION100
2.1654-2.23530.18452670.16174802X-RAY DIFFRACTION100
2.2353-2.31520.20052740.16444779X-RAY DIFFRACTION100
2.3152-2.40780.19392510.1714805X-RAY DIFFRACTION100
2.4078-2.51740.21672560.16664780X-RAY DIFFRACTION100
2.5174-2.65010.21062790.17044769X-RAY DIFFRACTION100
2.6501-2.81610.20472360.17584818X-RAY DIFFRACTION100
2.8161-3.03350.20542820.17964808X-RAY DIFFRACTION100
3.0335-3.33870.21772220.17434833X-RAY DIFFRACTION100
3.3387-3.82170.182640.16954816X-RAY DIFFRACTION100
3.8217-4.81410.17762400.15854855X-RAY DIFFRACTION100
4.8141-46.39090.18422550.18784888X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 13.3574 Å / Origin y: -0.2921 Å / Origin z: 22.6147 Å
111213212223313233
T0.0237 Å2-0.0025 Å2-0.0032 Å2-0.046 Å2-0.0066 Å2--0.0446 Å2
L0.163 °20.0606 °2-0.0559 °2-0.3165 °2-0.0639 °2--0.2554 °2
S0.0307 Å °-0.0244 Å °0 Å °-0.0165 Å °-0.0093 Å °-0.0236 Å °0.0023 Å °0.0575 Å °0.0006 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:610 ) ) OR ( CHAIN B AND ( RESID 8:487 OR RESID 603:610 ) )A8 - 486
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:610 ) ) OR ( CHAIN B AND ( RESID 8:487 OR RESID 603:610 ) )A603 - 610
3X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:610 ) ) OR ( CHAIN B AND ( RESID 8:487 OR RESID 603:610 ) )B8 - 487
4X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:610 ) ) OR ( CHAIN B AND ( RESID 8:487 OR RESID 603:610 ) )B603 - 610

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