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- PDB-4xjs: Human CD38 complexed with inhibitor 1 [6-fluoro-2-methyl-4-[(2,3,... -

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Basic information

Entry
Database: PDB / ID: 4xjs
TitleHuman CD38 complexed with inhibitor 1 [6-fluoro-2-methyl-4-[(2,3,6-trichlorobenzyl)amino]quinoline-8-carboxamide]
ComponentsADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1
KeywordsHydrolase / Transferase / CD38
Function / homology
Function and homology information


2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase / phosphorus-oxygen lyase activity / artery smooth muscle contraction / Nicotinate metabolism / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NADP+ nucleosidase activity / NAD metabolic process / NAD+ nucleotidase, cyclic ADP-ribose generating / negative regulation of bone resorption ...2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase / phosphorus-oxygen lyase activity / artery smooth muscle contraction / Nicotinate metabolism / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NADP+ nucleosidase activity / NAD metabolic process / NAD+ nucleotidase, cyclic ADP-ribose generating / negative regulation of bone resorption / response to hydroperoxide / long-term synaptic depression / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / B cell proliferation / response to retinoic acid / positive regulation of B cell proliferation / positive regulation of vasoconstriction / response to interleukin-1 / response to progesterone / female pregnancy / apoptotic signaling pathway / B cell receptor signaling pathway / positive regulation of insulin secretion / response to estradiol / negative regulation of neuron projection development / positive regulation of cytosolic calcium ion concentration / transferase activity / positive regulation of cell growth / basolateral plasma membrane / response to hypoxia / response to xenobiotic stimulus / negative regulation of DNA-templated transcription / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / cell surface / signal transduction / extracellular exosome / membrane / identical protein binding / plasma membrane
Similarity search - Function
ADP Ribosyl Cyclase; Chain A, domain 1 / ADP Ribosyl Cyclase; Chain A, domain 1 / ADP-ribosyl cyclase (CD38/157) / ADP-ribosyl cyclase / NAD(P)-binding Rossmann-like Domain / Up-down Bundle / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-733 / 5-O-phosphono-alpha-D-ribofuranose / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsShewchuk, L.M. / Deaton, D. / Stewart, E.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38.
Authors: Becherer, J.D. / Boros, E.E. / Carpenter, T.Y. / Cowan, D.J. / Deaton, D.N. / Haffner, C.D. / Jeune, M.R. / Kaldor, I.W. / Poole, J.C. / Preugschat, F. / Rheault, T.R. / Schulte, C.A. / ...Authors: Becherer, J.D. / Boros, E.E. / Carpenter, T.Y. / Cowan, D.J. / Deaton, D.N. / Haffner, C.D. / Jeune, M.R. / Kaldor, I.W. / Poole, J.C. / Preugschat, F. / Rheault, T.R. / Schulte, C.A. / Shearer, B.G. / Shearer, T.W. / Shewchuk, L.M. / Smalley, T.L. / Stewart, E.L. / Stuart, J.D. / Ulrich, J.C.
History
DepositionJan 9, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2015Group: Database references
Revision 1.2Sep 23, 2015Group: Database references
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / chem_comp ...atom_site / chem_comp / citation / pdbx_chem_comp_identifier / pdbx_struct_oper_list / struct_conn / struct_site / struct_site_gen
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp.mon_nstd_flag / _chem_comp.type / _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.ptnr2_label_atom_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,9613
Polymers30,3181
Non-polymers6432
Water41423
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.298, 64.424, 72.832
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 / 2'-phospho-ADP-ribosyl cyclase / 2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose ...2'-phospho-ADP-ribosyl cyclase / 2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase / 2'-phospho-cyclic-ADP-ribose transferase / ADP-ribosyl cyclase 1 / ADPRC 1 / Cyclic ADP-ribose hydrolase 1 / cADPr hydrolase 1 / T10


Mass: 30318.303 Da / Num. of mol.: 1 / Mutation: N100D, N164A, N209D, N219D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD38 / Production host: Pichia (fungus)
References: UniProt: P28907, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase, 2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase
#2: Chemical ChemComp-733 / 6-fluoro-2-methyl-4-[(2,3,6-trichlorobenzyl)amino]quinoline-8-carboxamide


Mass: 412.673 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H13Cl3FN3O
#3: Sugar ChemComp-HSX / 5-O-phosphono-alpha-D-ribofuranose / 5-O-phosphono-alpha-D-ribose / 5-O-phosphono-D-ribose / 5-O-phosphono-ribose


Type: D-saccharide, alpha linking / Mass: 230.110 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C5H11O8P
IdentifierTypeProgram
a-D-Ribf5PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 1.95 Å3/Da / Density % sol: 36.8 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Protein concentration was 7mgs/ml. Crystals were grown from 23% PEG3350, 0.1mM BisTrisPropane at 22 deg C (2+2uL drops over a 500uL well). Crystals were soaked with 5mM inhibitor for 24 ...Details: Protein concentration was 7mgs/ml. Crystals were grown from 23% PEG3350, 0.1mM BisTrisPropane at 22 deg C (2+2uL drops over a 500uL well). Crystals were soaked with 5mM inhibitor for 24 hours prior to data collection. Crystals were flash frozen in PFO.

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Jan 25, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.8→34.8 Å / Num. obs: 5790 / % possible obs: 98 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 29
Reflection shellResolution: 2.8→2.87 Å / Redundancy: 7 % / Rmerge(I) obs: 0.59 / Mean I/σ(I) obs: 4.8 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1YH3

1yh3


Resolution: 2.8→34.8 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.896 / SU B: 36.526 / SU ML: 0.351 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.439 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2634 293 4.8 %RANDOM
Rwork0.1863 5790 --
obs0.1899 5790 98.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 115.38 Å2 / Biso mean: 53.927 Å2 / Biso min: 14.79 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å2-0 Å2-0 Å2
2---0.12 Å20 Å2
3---0.11 Å2
Refinement stepCycle: final / Resolution: 2.8→34.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1886 0 39 23 1948
Biso mean--67.5 34.17 -
Num. residues----239
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0191999
X-RAY DIFFRACTIONr_bond_other_d0.0010.021785
X-RAY DIFFRACTIONr_angle_refined_deg1.2391.9532730
X-RAY DIFFRACTIONr_angle_other_deg0.79234121
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4275243
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.03825.22788
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.17515324
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.953155
X-RAY DIFFRACTIONr_chiral_restr0.0650.2299
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212237
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02453
X-RAY DIFFRACTIONr_mcbond_it1.2023.341960
X-RAY DIFFRACTIONr_mcbond_other1.1913.338959
X-RAY DIFFRACTIONr_mcangle_it1.9615.0041198
LS refinement shellResolution: 2.8→2.872 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 23 -
Rwork0.263 395 -
all-418 -
obs--99.52 %
Refinement TLS params.Method: refined / Details: Chain A catalytic domain / Origin x: -7.141 Å / Origin y: -14.844 Å / Origin z: 15.142 Å
111213212223313233
T0.1132 Å2-0.0313 Å2-0.0416 Å2-0.0917 Å20.0075 Å2--0.1935 Å2
L1.3648 °2-0.5353 °2-1.5292 °2-1.8582 °20.311 °2--3.5303 °2
S-0.1248 Å °0.0034 Å °0.0158 Å °0.1817 Å °0.0566 Å °0.2447 Å °0.108 Å °-0.1512 Å °0.0682 Å °

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