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- PDB-7ppe: CRYSTAL STRUCTURE OF NAMPT IN COMPLEX WITH COMPOUND 1 -

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Basic information

Entry
Database: PDB / ID: 7ppe
TitleCRYSTAL STRUCTURE OF NAMPT IN COMPLEX WITH COMPOUND 1
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 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-type TIM barrel
Similarity search - Domain/homology
Chem-7YK / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,92512
Polymers111,3042
Non-polymers1,62110
Water13,169731
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10520 Å2
ΔGint-86 kcal/mol
Surface area32400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.823, 106.771, 82.625
Angle α, β, γ (deg.)90.000, 96.350, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: PHE / Beg label comp-ID: PHE / End auth comp-ID: ASN / End label comp-ID: ASN / Refine code: _ / Auth seq-ID: 9 - 483 / Label seq-ID: 10 - 484

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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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.: 2
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.: 6 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-7YK / N-[4-[(4R)-4-methyl-1-(oxan-4-yl)-6-oxidanylidene-4,5-dihydropyridazin-3-yl]phenyl]-1,3-dihydropyrrolo[3,4-c]pyridine-2-carboxamide


Mass: 433.503 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H27N5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 731 / 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: 2.4 Å3/Da / Density % sol: 48.66 %
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% GLYCEROL

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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: Nov 20, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.86→46.37 Å / Num. obs: 87622 / % possible obs: 98.9 % / Redundancy: 3.35 % / Biso Wilson estimate: 28.1 Å2 / CC1/2: 0.995 / Rrim(I) all: 0.107 / Rsym value: 0.09 / Net I/σ(I): 9.5
Reflection shellResolution: 1.86→1.97 Å / Redundancy: 2.1 % / Mean I/σ(I) obs: 2.1 / Num. unique obs: 13570 / CC1/2: 0.75 / Rrim(I) all: 0.614 / Rsym value: 0.515 / % possible all: 95

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSVERSION January 10, 2014data reduction
pointlessversion 1.9.16data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GVJ

2gvj


Resolution: 1.86→46.37 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.953 / SU B: 5.759 / SU ML: 0.086 / SU R Cruickshank DPI: 0.115 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.115 / ESU R Free: 0.112 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES: WITH TLS ADDED.
RfactorNum. reflection% reflectionSelection details
Rfree0.1865 4382 5 %RANDOM
Rwork0.148 ---
obs0.1499 83240 98.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 102.19 Å2 / Biso mean: 23.113 Å2 / Biso min: 11.09 Å2
Baniso -1Baniso -2Baniso -3
1-0.98 Å20 Å2-0.81 Å2
2--0.34 Å20 Å2
3----1.11 Å2
Refinement stepCycle: final / Resolution: 1.86→46.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7457 0 106 731 8294
Biso mean--40.9 31.76 -
Num. residues----932
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0137833
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177395
X-RAY DIFFRACTIONr_angle_refined_deg1.7521.65710632
X-RAY DIFFRACTIONr_angle_other_deg1.5151.59817118
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9855952
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.9323.77382
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.554151370
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7351528
X-RAY DIFFRACTIONr_chiral_restr0.0960.2991
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.028768
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021744
Refine LS restraints NCS

Ens-ID: 1 / Number: 15447 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.07 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.86→1.904 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.269 293 -
Rwork0.247 5550 -
obs--89.22 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.27370.02710.10730.5349-0.37710.72340.00820.0295-0.0381-0.0984-0.0029-0.07140.06220.0348-0.00530.02810.00880.02320.0201-0.0140.061414.49-7.66914.013
20.34090.1187-0.07410.592-0.25240.48980.0279-0.01150.03210.0536-0.0094-0.0412-0.06640.0362-0.01860.0133-0.01160.00720.0191-0.01710.051812.8197.72930.748
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A9 - 484
2X-RAY DIFFRACTION2B9 - 483

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