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- PDB-7ppg: CRYSTAL STRUCTURE OF NAMPT IN COMPLEX WITH COMPOUND 9 -

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Basic information

Entry
Database: PDB / ID: 7ppg
TitleCRYSTAL STRUCTURE OF NAMPT IN COMPLEX WITH COMPOUND 9
ComponentsNicotinamide phosphoribosyltransferase
KeywordsTRANSFERASE / SMALL MOLECULE INHIBITOR / NMPRTASE
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
Chem-7YX / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.13 Å
AuthorsHillig, R.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioconjug.Chem. / Year: 2022
Title: A Novel NAMPT Inhibitor-Based Antibody-Drug Conjugate Payload Class for Cancer Therapy.
Authors: Bohnke, N. / Berger, M. / Griebenow, N. / Rottmann, A. / Erkelenz, M. / Hammer, S. / Berndt, S. / Gunther, J. / Wengner, A.M. / Stelte-Ludwig, B. / Mahlert, C. / Greven, S. / Dietz, L. / ...Authors: Bohnke, N. / Berger, M. / Griebenow, N. / Rottmann, A. / Erkelenz, M. / Hammer, S. / Berndt, S. / Gunther, J. / Wengner, A.M. / Stelte-Ludwig, B. / Mahlert, C. / Greven, S. / Dietz, L. / Jorissen, H. / Barak, N. / Bomer, U. / Hillig, R.C. / Eberspaecher, U. / Weiske, J. / Giese, A. / Mumberg, D. / Nising, C.F. / Weinmann, H. / Sommer, A.
History
DepositionSep 13, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 15, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 22, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)225,19119
Polymers222,6084
Non-polymers2,58315
Water23,7081316
1
A: Nicotinamide phosphoribosyltransferase
B: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,61010
Polymers111,3042
Non-polymers1,3068
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9940 Å2
ΔGint-51 kcal/mol
Surface area32330 Å2
MethodPISA
2
C: Nicotinamide phosphoribosyltransferase
D: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,5819
Polymers111,3042
Non-polymers1,2777
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9770 Å2
ΔGint-67 kcal/mol
Surface area32300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.956, 106.180, 121.340
Angle α, β, γ (deg.)90.000, 96.530, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: PHE / Beg label comp-ID: PHE / End auth comp-ID: ILE / End label comp-ID: ILE / Refine code: _ / Auth seq-ID: 9 - 484 / Label seq-ID: 10 - 485

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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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: 55651.988 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: N-terminal Gly is a cloning artifact, stems from TEV cleavage site
Source: (gene. exp.) Homo sapiens (human) / Gene: NAMPT, PBEF, PBEF1 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P43490, nicotinamide phosphoribosyltransferase
#2: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: PO4
#3: Chemical
ChemComp-7YX / N-[4-[(4R)-1-cyclopentyl-4-methyl-6-oxidanylidene-4,5-dihydropyridazin-3-yl]phenyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide


Mass: 417.503 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H27N5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1316 / 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: 2.39 Å3/Da / Density % sol: 48.43 %
Description: Crescent-shaped, plate-shaped crystals, often with very uneven surfaces
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.6
Details: 1 microliter of protein mixed with 1 microliter of reservoir buffer (27-31% PEG 3350 (w/v), 200 mM NaCl, 100 mM sodium dihydrogen phosphate pH 7.6) incubated for 5 min, then streak seeded ...Details: 1 microliter of protein mixed with 1 microliter of reservoir buffer (27-31% PEG 3350 (w/v), 200 mM NaCl, 100 mM sodium dihydrogen phosphate pH 7.6) incubated for 5 min, then streak seeded (with crystals obtained previously under identical conditions). Ligand added prior to crystallization (2 MILLIMOLAR FROM 100 MILLIMOLAR STOCK IN DMSO) and incubated for 1.5 h at 277 K. CRYO BUFFER consisted of RESERVOIR supplemented WITH 2 MILLIMOLAR INHIBITOR AND 15% ETHYLENGLYCOL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 28, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.13→48.59 Å / Num. obs: 114934 / % possible obs: 98 % / Redundancy: 2.67 % / Biso Wilson estimate: 24.9 Å2 / CC1/2: 0.994 / Rrim(I) all: 0.151 / Rsym value: 0.121 / Net I/σ(I): 6.89
Reflection shellResolution: 2.13→2.26 Å / Redundancy: 2.7 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 18131 / CC1/2: 0.854 / Rrim(I) all: 0.57 / Rsym value: 0.459 / % possible all: 96.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSVERSION January 10, 2014data reduction
pointlessversion 1.9.12data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GVJ

2gvj


Resolution: 2.13→48.59 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.897 / SU B: 8.165 / SU ML: 0.21 / SU R Cruickshank DPI: 0.3398 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.34 / ESU R Free: 0.256 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES: REFINED INDIVIDUALLY.
RfactorNum. reflection% reflectionSelection details
Rfree0.3025 5747 5 %RANDOM
Rwork0.2528 ---
obs0.2553 109187 97.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 155.16 Å2 / Biso mean: 20.514 Å2 / Biso min: 0.5 Å2
Baniso -1Baniso -2Baniso -3
1--0.76 Å2-0 Å2-0.65 Å2
2---0.2 Å20 Å2
3---1.08 Å2
Refinement stepCycle: final / Resolution: 2.13→48.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14937 0 175 1329 16441
Biso mean--24.7 25.74 -
Num. residues----1867
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01315507
X-RAY DIFFRACTIONr_bond_other_d0.0020.01714654
X-RAY DIFFRACTIONr_angle_refined_deg1.4221.65721022
X-RAY DIFFRACTIONr_angle_other_deg1.2861.59733893
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.90751867
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.73523.842747
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.573152698
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.371552
X-RAY DIFFRACTIONr_chiral_restr0.0680.21968
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0217325
X-RAY DIFFRACTIONr_gen_planes_other0.0010.023439
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A153240.08
12B153240.08
21A154910.06
22C154910.06
31A152640.08
32D152640.08
41B153770.08
42C153770.08
51B154110.06
52D154110.06
61C152420.08
62D152420.08
LS refinement shellResolution: 2.13→2.182 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.342 401 -
Rwork0.318 7614 -
obs--92.77 %

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