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- PDB-4wq6: The crystal structure of human Nicotinamide phosphoribosyltransfe... -

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Basic information

Entry
Database: PDB / ID: 4wq6
TitleThe crystal structure of human Nicotinamide phosphoribosyltransferase (NAMPT) in complex with N-(4-{(S)-[1-(2-methylpropyl)piperidin-4-yl]sulfinyl}benzyl)furo[2,3-c]pyridine-2-carboxamide inhibitor (compound 21)
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-3TQ / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.72 Å
AuthorsLi, D. / Wang, W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility.
Authors: Zak, M. / Liederer, B.M. / Sampath, D. / Yuen, P.W. / Bair, K.W. / Baumeister, T. / Buckmelter, A.J. / Clodfelter, K.H. / Cheng, E. / Crocker, L. / Fu, B. / Han, B. / Li, G. / Ho, Y.C. / ...Authors: Zak, M. / Liederer, B.M. / Sampath, D. / Yuen, P.W. / Bair, K.W. / Baumeister, T. / Buckmelter, A.J. / Clodfelter, K.H. / Cheng, E. / Crocker, L. / Fu, B. / Han, B. / Li, G. / Ho, Y.C. / Lin, J. / Liu, X. / Ly, J. / O'Brien, T. / Reynolds, D.J. / Skelton, N. / Smith, C.C. / Tay, S. / Wang, W. / Wang, Z. / Xiao, Y. / Zhang, L. / Zhao, G. / Zheng, X. / Dragovich, P.S.
History
DepositionOct 21, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 11, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation

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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)115,95121
Polymers113,8852
Non-polymers2,06619
Water11,241624
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12180 Å2
ΔGint-24 kcal/mol
Surface area32740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.621, 106.839, 83.086
Angle α, β, γ (deg.)90.00, 96.64, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Nicotinamide phosphoribosyltransferase / 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-3TQ / N-(4-{(S)-[1-(2-methylpropyl)piperidin-4-yl]sulfinyl}benzyl)furo[2,3-c]pyridine-2-carboxamide


Mass: 439.570 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H29N3O3S
#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.: 624 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.35 Å3/Da / Density % sol: 47.59 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop
Details: crystals were grown from 0.2uL + 0.2uL drops containing 6mg/mL Nampt, 0.1M Sodium phosphate, 25-29% polyethylene glycol 3350, 0.2M NaCl, 1mM compound
PH range: 8.6-9.0

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97922 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 13, 2012
RadiationMonochromator: double crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97922 Å / Relative weight: 1
ReflectionResolution: 1.72→50 Å / Num. all: 27924 / Num. obs: 25523 / % possible obs: 0.914 % / Redundancy: 4 % / Net I/σ(I): 14.1

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Processing

SoftwareName: PHENIX / Version: (phenix.refine: 1.9_1692) / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3DHF

3dhf


Resolution: 1.72→50 Å / SU ML: 0.15 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 19.51 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1883 5156 5.05 %5% Random selection
Rwork0.163 ---
obs0.1643 -91.17 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.72→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7519 0 134 624 8277
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0067818
X-RAY DIFFRACTIONf_angle_d1.02110568
X-RAY DIFFRACTIONf_dihedral_angle_d12.8382871
X-RAY DIFFRACTIONf_chiral_restr0.0431149
X-RAY DIFFRACTIONf_plane_restr0.0051336
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7169-1.73640.2518900.21181806X-RAY DIFFRACTION50
1.7364-1.75680.23951070.19512023X-RAY DIFFRACTION58
1.7568-1.77830.21411280.19542219X-RAY DIFFRACTION63
1.7783-1.80080.25951310.19162392X-RAY DIFFRACTION69
1.8008-1.82450.22271400.19192670X-RAY DIFFRACTION76
1.8245-1.84950.21821780.18172927X-RAY DIFFRACTION84
1.8495-1.87590.2361760.17823411X-RAY DIFFRACTION96
1.8759-1.90390.2021850.17653434X-RAY DIFFRACTION97
1.9039-1.93360.20491690.16683437X-RAY DIFFRACTION97
1.9336-1.96530.21461630.16873427X-RAY DIFFRACTION97
1.9653-1.99920.19451830.16683398X-RAY DIFFRACTION97
1.9992-2.03560.21271670.16343461X-RAY DIFFRACTION97
2.0356-2.07470.19281710.15983462X-RAY DIFFRACTION97
2.0747-2.1170.19531820.15973457X-RAY DIFFRACTION98
2.117-2.16310.17811910.15953431X-RAY DIFFRACTION97
2.1631-2.21340.19011760.15333468X-RAY DIFFRACTION98
2.2134-2.26870.18831970.15843424X-RAY DIFFRACTION97
2.2687-2.330.1971800.1573472X-RAY DIFFRACTION97
2.33-2.39860.19671910.15893408X-RAY DIFFRACTION98
2.3986-2.4760.19771850.16053448X-RAY DIFFRACTION98
2.476-2.56450.20381840.163471X-RAY DIFFRACTION98
2.5645-2.66710.18021830.16473499X-RAY DIFFRACTION98
2.6671-2.78840.20471900.16923472X-RAY DIFFRACTION98
2.7884-2.93540.22022130.17653461X-RAY DIFFRACTION99
2.9354-3.11920.17131880.16793468X-RAY DIFFRACTION98
3.1192-3.35980.2031990.17013509X-RAY DIFFRACTION98
3.3598-3.69760.17061810.15773447X-RAY DIFFRACTION98
3.6976-4.23190.15351590.14423518X-RAY DIFFRACTION98
4.2319-5.32870.14321780.14143436X-RAY DIFFRACTION96
5.3287-34.93650.17191910.17393440X-RAY DIFFRACTION95
Refinement TLS params.Method: refined / Origin x: 13.4154 Å / Origin y: -0.2623 Å / Origin z: 22.7117 Å
111213212223313233
T0.0371 Å2-0.004 Å2-0.0039 Å2-0.0492 Å2-0.0027 Å2--0.0484 Å2
L0.1388 °20.0558 °2-0.0474 °2-0.2761 °2-0.0816 °2--0.2491 °2
S0.0225 Å °-0.0212 Å °-0.0039 Å °-0.0162 Å °-0.0048 Å °-0.0165 Å °0.0001 Å °0.0353 Å °0.0001 Å °
Refinement TLS groupSelection details: chain A or chain B or chain S or chain L

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