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- PDB-4lvd: Fragment-based Identification of Amides Derived From trans-2-(Pyr... -

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Basic information

Entry
Database: PDB / ID: 4lvd
TitleFragment-based Identification of Amides Derived From trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)
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
N-(4-nitrophenyl)cyclopropanecarboxamide / PHOSPHATE ION / Nicotinamide phosphoribosyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsGiannetti, A.M. / Zheng, X. / Skelton, N. / Wang, W. / Bravo, B. / Feng, Y. / Gunzner-Toste, J. / Ho, Y. / Hua, R. / Wang, C. ...Giannetti, A.M. / Zheng, X. / Skelton, N. / Wang, W. / Bravo, B. / Feng, Y. / Gunzner-Toste, J. / Ho, Y. / Hua, R. / Wang, C. / Zhao, Q. / Liederer, B.M. / Liu, Y. / O'Brien, T. / Oeh, J. / Sampath, D. / Shen, Y. / Wang, L. / Wu, H. / Xiao, Y. / Yuen, P. / Zak, M. / Zhao, G. / Dragovich, P.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Identification of amides derived from 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
Authors: Zheng, X. / Bair, K.W. / Bauer, P. / Baumeister, T. / Bowman, K.K. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Feng, Y. / Han, B. / Ho, Y.C. / Kley, N. / Li, H. / Liang, X. / ...Authors: Zheng, X. / Bair, K.W. / Bauer, P. / Baumeister, T. / Bowman, K.K. / Buckmelter, A.J. / Caligiuri, M. / Clodfelter, K.H. / Feng, Y. / Han, B. / Ho, Y.C. / Kley, N. / Li, H. / Liang, X. / Liederer, B.M. / Lin, J. / Ly, J. / O'Brien, T. / Oeh, J. / Oh, A. / Reynolds, D.J. / Sampath, D. / Sharma, G. / Skelton, N. / Smith, C.C. / Tremayne, J. / Wang, L. / Wang, W. / Wang, Z. / Wu, H. / Wu, J. / Xiao, Y. / Yang, G. / Yuen, P.W. / Zak, M. / Dragovich, P.S.
History
DepositionJul 26, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2013Group: Database references
Revision 1.2Jan 24, 2018Group: Advisory / Structure summary / Category: audit_author / pdbx_unobs_or_zero_occ_atoms / Item: _audit_author.name
Revision 1.3Feb 28, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms / 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
B: Nicotinamide phosphoribosyltransferase
A: Nicotinamide phosphoribosyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,7399
Polymers113,8852
Non-polymers8547
Water17,817989
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9650 Å2
ΔGint-68 kcal/mol
Surface area33000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.423, 106.039, 83.055
Angle α, β, γ (deg.)90.00, 96.26, 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-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-1EB / N-(4-nitrophenyl)cyclopropanecarboxamide


Mass: 206.198 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H10N2O3
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 989 / 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: 2.32 Å3/Da / Density % sol: 47.04 %
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, pH 8.6, VAPOR DIFFUSION, HANGING DROP, temperature 292K

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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 16, 2012
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97922 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. all: 104939 / Num. obs: 104834 / % possible obs: 99.9 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 1.75→1.81 Å / % possible all: 100

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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 / Resolution: 1.75→30.995 Å / SU ML: 0.21 / σ(F): 1.34 / Phase error: 21.6 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2128 5239 5 %5% random
Rwork0.1776 ---
all0.2128 104939 --
obs0.1793 104785 99.62 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.75→30.995 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7510 0 54 989 8553
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077754
X-RAY DIFFRACTIONf_angle_d1.04710508
X-RAY DIFFRACTIONf_dihedral_angle_d13.0112857
X-RAY DIFFRACTIONf_chiral_restr0.0731148
X-RAY DIFFRACTIONf_plane_restr0.0051335
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.76680.30691890.27353024X-RAY DIFFRACTION91
1.7668-1.78760.2971850.26053237X-RAY DIFFRACTION100
1.7876-1.80940.27361940.2513320X-RAY DIFFRACTION100
1.8094-1.83230.29731720.23963336X-RAY DIFFRACTION100
1.8323-1.85640.26361410.22323311X-RAY DIFFRACTION100
1.8564-1.88180.2521980.21623320X-RAY DIFFRACTION100
1.8818-1.90870.2271600.20233317X-RAY DIFFRACTION100
1.9087-1.93720.2541750.19223358X-RAY DIFFRACTION100
1.9372-1.96750.25891810.19653301X-RAY DIFFRACTION100
1.9675-1.99970.23941850.18673287X-RAY DIFFRACTION100
1.9997-2.03420.22681620.18583364X-RAY DIFFRACTION100
2.0342-2.07120.23731510.18623364X-RAY DIFFRACTION100
2.0712-2.1110.22441650.18353294X-RAY DIFFRACTION100
2.111-2.15410.21211790.17773317X-RAY DIFFRACTION100
2.1541-2.20090.21321670.17733334X-RAY DIFFRACTION100
2.2009-2.25210.21251820.16973338X-RAY DIFFRACTION100
2.2521-2.30840.19611690.17253316X-RAY DIFFRACTION100
2.3084-2.37080.21041880.17453296X-RAY DIFFRACTION100
2.3708-2.44050.21421740.16893362X-RAY DIFFRACTION100
2.4405-2.51930.19351670.17053335X-RAY DIFFRACTION100
2.5193-2.60930.24621880.17713310X-RAY DIFFRACTION100
2.6093-2.71370.2161980.17273298X-RAY DIFFRACTION100
2.7137-2.83710.20961730.17523321X-RAY DIFFRACTION100
2.8371-2.98660.20041770.18113336X-RAY DIFFRACTION100
2.9866-3.17350.18441880.16813329X-RAY DIFFRACTION100
3.1735-3.41820.22891630.17473341X-RAY DIFFRACTION100
3.4182-3.76170.19711540.16223381X-RAY DIFFRACTION100
3.7617-4.30480.15971450.14943367X-RAY DIFFRACTION100
4.3048-5.41890.15971760.14893340X-RAY DIFFRACTION100
5.4189-30.9950.21561930.18053392X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 12.0407 Å / Origin y: -7.3522 Å / Origin z: 18.7703 Å
111213212223313233
T0.0679 Å20.0008 Å20.0019 Å2-0.0709 Å20.0065 Å2--0.0721 Å2
L0.1106 °2-0.007 °2-0.0029 °2-0.2967 °20.0629 °2--0.2813 °2
S0.0113 Å °-0.0043 Å °-0.001 Å °0.0399 Å °0.0107 Å °0.0264 Å °0.0062 Å °-0.0203 Å °-0.0185 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1203 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1186 ) )A8 - 486
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1203 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1186 ) )A603
3X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1203 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1186 ) )A601 - 602
4X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1203 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1186 ) )A701 - 1203
5X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1203 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1186 ) )B8 - 486
6X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1203 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1186 ) )B603
7X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1203 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1186 ) )B601 - 602
8X-RAY DIFFRACTION1( CHAIN A AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1203 ) ) OR ( CHAIN B AND ( RESID 8:486 OR RESID 603:603 OR RESID 601:602 OR RESID 701:1186 ) )B701 - 1186

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