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- PDB-8ivu: Crystal Structure of Human NAMPT in complex with A4276 -

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Basic information

Entry
Database: PDB / ID: 8ivu
TitleCrystal Structure of Human NAMPT in complex with A4276
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTRANSFERASE / NAMPT / Inhibitor / Complex / Cancer
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-type TIM barrel
Similarity search - Domain/homology
PHOSPHATE ION / Chem-SJ6 / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09000922463 Å
AuthorsKang, B.G. / Cha, S.S.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea) Korea, Republic Of
CitationJournal: Theranostics / Year: 2023
Title: Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy.
Authors: Kim, M. / Kim, H. / Kang, B.G. / Lee, J. / Kim, T. / Lee, H. / Jung, J. / Oh, M.J. / Seo, S. / Ryu, M.J. / Sung, Y. / Lee, Y. / Yeom, J. / Han, G. / Cha, S.S. / Jung, H. / Kim, H.S.
History
DepositionMar 28, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Nicotinamide phosphoribosyltransferase
B: Nicotinamide phosphoribosyltransferase
C: Nicotinamide phosphoribosyltransferase
D: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)224,89320
Polymers222,3804
Non-polymers2,51316
Water12,791710
1
A: Nicotinamide phosphoribosyltransferase
B: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,44610
Polymers111,1902
Non-polymers1,2578
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10020 Å2
ΔGint-82 kcal/mol
Surface area32420 Å2
MethodPISA
2
C: Nicotinamide phosphoribosyltransferase
D: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,44610
Polymers111,1902
Non-polymers1,2578
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10060 Å2
ΔGint-83 kcal/mol
Surface area32250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.560, 116.690, 195.410
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
31
41

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLULYSLYSchain 'A'AA8 - 428 - 42
12LYSLYSASNASNchain 'A'AA53 - 48353 - 483
23GLUGLULYSLYSchain 'B'BB8 - 428 - 42
24LYSLYSASNASNchain 'B'BB53 - 48353 - 483
35GLUGLULYSLYSchain 'C'CC8 - 428 - 42
36LYSLYSASNASNchain 'C'CC53 - 48353 - 483
47GLUGLULYSLYSchain 'D'DD8 - 428 - 42
48LYSLYSASNASNchain 'D'DD53 - 48353 - 483

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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: 55594.938 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NAMPT, PBEF, PBEF1 / Production host: Escherichia coli B (bacteria)
References: UniProt: P43490, nicotinamide phosphoribosyltransferase
#2: Chemical
ChemComp-SJ6 / N-[[4-(6-methyl-1,3-benzoxazol-2-yl)phenyl]methyl]pyridine-3-carboxamide


Mass: 343.379 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H17N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 710 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.47 Å3/Da / Density % sol: 50.16 %
Crystal growTemperature: 283.15 K / Method: microbatch / pH: 7
Details: 0.1M sodium phosphate pH 7.0, 0.2M sodium chloride, 25% (w/v) polyethylene glycol (PEG) 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 5C (4A) / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.09→29.71 Å / Num. obs: 132238 / % possible obs: 99.9 % / Redundancy: 13.8 % / Biso Wilson estimate: 40.4049994066 Å2 / Rrim(I) all: 0.203 / Net I/σ(I): 8.8
Reflection shellResolution: 2.09→2.15 Å / Num. unique obs: 12302 / CC1/2: 0.594

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Processing

Software
NameVersionClassification
Cootmodel building
PHENIX1.11.1-2575-000refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.09000922463→29.7083970676 Å / SU ML: 0.268400200344 / Cross valid method: NONE / σ(F): 1.34752066661 / Phase error: 25.7579814875
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.231333965665 6612 5.00075631523 %
Rwork0.20405167256 125608 -
obs0.205423269196 132220 99.9780716678 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 46.5320590098 Å2
Refinement stepCycle: LAST / Resolution: 2.09000922463→29.7083970676 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14920 0 164 710 15794
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024866121668815436
X-RAY DIFFRACTIONf_angle_d0.58034821505320920
X-RAY DIFFRACTIONf_chiral_restr0.04400273587742268
X-RAY DIFFRACTIONf_plane_restr0.003603027475592648
X-RAY DIFFRACTIONf_dihedral_angle_d11.76974847649096
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.09001-2.11380.357788282122170.3009569691434138X-RAY DIFFRACTION99.9770431589
2.1138-2.13860.3410807206792170.3096250211754111X-RAY DIFFRACTION99.9538106236
2.1386-2.16470.3143557254162190.3018636765034161X-RAY DIFFRACTION99.9771741612
2.1647-2.19210.3030868784432170.2936652876614132X-RAY DIFFRACTION99.9310661765
2.1921-2.22090.3507765086952190.2884367358614146X-RAY DIFFRACTION99.9313186813
2.2209-2.25130.3016820910772190.2812903322744178X-RAY DIFFRACTION99.977262392
2.2513-2.28350.3213967338552160.2782026180764104X-RAY DIFFRACTION100
2.2835-2.31760.2780127612862210.2666807674094179X-RAY DIFFRACTION99.9772778914
2.3176-2.35380.2944093337962160.2553559557764105X-RAY DIFFRACTION100
2.3538-2.39230.2860544267452190.2612706633964169X-RAY DIFFRACTION100
2.3923-2.43360.3117725029642190.2657783970994161X-RAY DIFFRACTION100
2.4336-2.47780.2669126814092200.2572045515264184X-RAY DIFFRACTION100
2.4778-2.52540.3212969699622170.2528467419194121X-RAY DIFFRACTION100
2.5254-2.57690.27224171212210.2518021451034203X-RAY DIFFRACTION99.9774011299
2.5769-2.63290.3105215453272180.2474849636954145X-RAY DIFFRACTION100
2.6329-2.69410.2818952196052190.2451562882164158X-RAY DIFFRACTION100
2.6941-2.76150.256963350832190.2436864377214163X-RAY DIFFRACTION100
2.7615-2.83610.3295385665972200.2428443138164172X-RAY DIFFRACTION100
2.8361-2.91950.292781242722200.2515336483584188X-RAY DIFFRACTION100
2.9195-3.01360.2691052327462210.2378944425654187X-RAY DIFFRACTION99.97731912
3.0136-3.12120.2328056304982200.2217415559854177X-RAY DIFFRACTION100
3.1212-3.2460.2669473725182210.2239844470154204X-RAY DIFFRACTION100
3.246-3.39360.2505997173572200.2226749127114183X-RAY DIFFRACTION100
3.3936-3.57220.2284394495772210.2044240269134195X-RAY DIFFRACTION100
3.5722-3.79560.2216839025612230.188401156054241X-RAY DIFFRACTION100
3.7956-4.0880.1816418100352220.1660936625724210X-RAY DIFFRACTION99.9774419129
4.088-4.49810.1673569015062230.150408746194244X-RAY DIFFRACTION100
4.4981-5.14610.167012372642250.1421443907614275X-RAY DIFFRACTION99.977782715
5.1461-6.47240.180169196662270.166781144234310X-RAY DIFFRACTION100
6.4724-100.168541073142360.1520852220074464X-RAY DIFFRACTION99.7241671971

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