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- PDB-4lww: Discovery of Potent and Efficacious Cyanoguanidine-containing Nic... -

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Basic information

Entry
Database: PDB / ID: 4lww
TitleDiscovery of Potent and Efficacious Cyanoguanidine-containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / 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 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-LWW / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.641 Å
AuthorsZheng, X. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Han, B. / Ho, Y. / Kley, N. / Lin, J. / Reynoids, D.J. ...Zheng, X. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Han, B. / Ho, Y. / Kley, N. / Lin, J. / Reynoids, D.J. / Sharma, G. / Smith, C.C. / Wang, Z. / Dragovich, P.S. / Oh, A. / Wang, W. / Zak, M. / Wang, L. / Yuen, P. / Bair, K.W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.
Authors: Zheng, X. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Han, B. / Ho, Y.C. / Kley, N. / Lin, J. / Reynolds, D.J. / Sharma, G. / Smith, C.C. / Wang, Z. / Dragovich, ...Authors: Zheng, X. / Baumeister, T. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Han, B. / Ho, Y.C. / Kley, N. / Lin, J. / Reynolds, D.J. / Sharma, G. / Smith, C.C. / Wang, Z. / Dragovich, P.S. / Oh, A. / Wang, W. / Zak, M. / Wang, Y. / Yuen, P.W. / Bair, K.W.
History
DepositionJul 28, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)116,22727
Polymers113,8852
Non-polymers2,34225
Water20,0331112
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13500 Å2
ΔGint-5 kcal/mol
Surface area32470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.426, 106.287, 83.049
Angle α, β, γ (deg.)90.00, 96.45, 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-LWW / N-(4-(phenylsulfonyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide


Mass: 391.443 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H17N3O3S
#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.: 19 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1112 / 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: 47.14 %
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: May 30, 2013
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: 1.64→50 Å / Num. all: 126639 / Num. obs: 125879 / % possible obs: 99.4 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Biso Wilson estimate: 15.97 Å2
Reflection shellResolution: 1.64→1.7 Å / % possible all: 98.4

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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
Starting model: 3DHF

3dhf


Resolution: 1.641→46.254 Å / SU ML: 0.16 / σ(F): 1.34 / Phase error: 18.54 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1794 6318 5.02 %5% random
Rwork0.1537 ---
all0.1794 126639 --
obs0.155 125827 99.09 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.641→46.254 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7533 0 152 1112 8797
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0067903
X-RAY DIFFRACTIONf_angle_d1.0710681
X-RAY DIFFRACTIONf_dihedral_angle_d12.72906
X-RAY DIFFRACTIONf_chiral_restr0.0721154
X-RAY DIFFRACTIONf_plane_restr0.0051355
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6412-1.65990.2691880.24063625X-RAY DIFFRACTION91
1.6599-1.67940.26812120.22574005X-RAY DIFFRACTION99
1.6794-1.69990.25832010.20833894X-RAY DIFFRACTION98
1.6999-1.72140.25212180.19983956X-RAY DIFFRACTION99
1.7214-1.74410.24372010.19283957X-RAY DIFFRACTION99
1.7441-1.7680.22642170.18433982X-RAY DIFFRACTION99
1.768-1.79320.20732210.18213926X-RAY DIFFRACTION99
1.7932-1.820.23271900.17893979X-RAY DIFFRACTION99
1.82-1.84840.23222160.17563956X-RAY DIFFRACTION99
1.8484-1.87870.22212130.17353966X-RAY DIFFRACTION99
1.8787-1.91110.20022150.16563954X-RAY DIFFRACTION99
1.9111-1.94590.19462060.15614006X-RAY DIFFRACTION99
1.9459-1.98330.19251740.15643993X-RAY DIFFRACTION99
1.9833-2.02380.18182150.15113989X-RAY DIFFRACTION99
2.0238-2.06780.16411950.15874004X-RAY DIFFRACTION99
2.0678-2.11590.19462010.15853990X-RAY DIFFRACTION99
2.1159-2.16880.19272540.15343969X-RAY DIFFRACTION100
2.1688-2.22750.18292210.15143999X-RAY DIFFRACTION100
2.2275-2.2930.1652300.14413957X-RAY DIFFRACTION100
2.293-2.3670.17472060.15194027X-RAY DIFFRACTION100
2.367-2.45160.17832060.14474016X-RAY DIFFRACTION100
2.4516-2.54980.17742290.14723983X-RAY DIFFRACTION100
2.5498-2.66580.17682150.154034X-RAY DIFFRACTION100
2.6658-2.80630.18322000.1564030X-RAY DIFFRACTION100
2.8063-2.98210.19092420.16414002X-RAY DIFFRACTION100
2.9821-3.21230.17892010.14924051X-RAY DIFFRACTION100
3.2123-3.53550.16762010.14734034X-RAY DIFFRACTION100
3.5355-4.04680.14412170.12924053X-RAY DIFFRACTION100
4.0468-5.09750.13961890.12364078X-RAY DIFFRACTION100
5.0975-46.27230.15172240.15954094X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 13.4314 Å / Origin y: 1.1559 Å / Origin z: 22.6843 Å
111213212223313233
T0.0673 Å2-0.0026 Å2-0.0015 Å2-0.0695 Å2-0.0042 Å2--0.0686 Å2
L0.1181 °20.0226 °2-0.0223 °2-0.2344 °2-0.0694 °2--0.229 °2
S0.0135 Å °-0.0063 Å °0.0013 Å °-0.0259 Å °0.0033 Å °-0.0166 Å °0.0031 Å °0.0256 Å °0.0402 Å °
Refinement TLS groupSelection details: chain A or chain B

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