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- PDB-3u4h: CD38 structure-based inhibitor design using the N1-cyclic inosine... -

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Basic information

Entry
Database: PDB / ID: 3u4h
TitleCD38 structure-based inhibitor design using the N1-cyclic inosine 5'-diphosphate ribose template
ComponentsADP-ribosyl cyclase 1Cyclic ADP-ribose
KeywordsHYDROLASE/HYDROLASE INHIBITOR / non-hydrolyzable inhibitor / two domains / cADPR cyclization / hydrolysis / 8-amino-N1-cIDPR / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


phosphorus-oxygen lyase activity / 2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase / artery smooth muscle contraction / Nicotinate metabolism / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD metabolic process / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / negative regulation of bone resorption ...phosphorus-oxygen lyase activity / 2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase / artery smooth muscle contraction / Nicotinate metabolism / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD metabolic process / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / 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 / negative regulation of neuron projection development / response to estradiol / 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
8-Amino-N1-Cyclic Inosine 5'-Diphosphoribose / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.878 Å
AuthorsLiu, Q. / Hao, Q. / Lee, H.C. / Graeff, R.
CitationJournal: Plos One / Year: 2013
Title: CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5'-Diphosphate Ribose Template
Authors: Moreau, C. / Liu, Q. / Graeff, R. / Wagner, G.K. / Thomas, M.P. / Swarbrick, J.M. / Shuto, S. / Lee, H.C. / Hao, Q. / Potter, B.V.L.
History
DepositionOct 8, 2011Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 10, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2013Group: Database references
Revision 1.2Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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
A: ADP-ribosyl cyclase 1
B: ADP-ribosyl cyclase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,8754
Polymers60,7612
Non-polymers1,1152
Water4,522251
1
A: ADP-ribosyl cyclase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,9382
Polymers30,3801
Non-polymers5571
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: ADP-ribosyl cyclase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,9382
Polymers30,3801
Non-polymers5571
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.713, 51.459, 67.755
Angle α, β, γ (deg.)72.85, 89.13, 83.18
Int Tables number1
Space group name H-MP1

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Components

#1: Protein ADP-ribosyl cyclase 1 / Cyclic ADP-ribose / Cyclic ADP-ribose hydrolase 1 / cADPr hydrolase 1 / T10


Mass: 30380.393 Da / Num. of mol.: 2 / Fragment: extracellular domain, enzymatic domain / Mutation: Q49T, N100D, N164D, N209D, N219D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD38 / Production host: Pichia Pastoris (fungus) / References: UniProt: P28907, NAD+ glycohydrolase
#2: Chemical ChemComp-C8R / 8-Amino-N1-Cyclic Inosine 5'-Diphosphoribose


Mass: 557.300 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H21N5O14P2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 251 / 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: 2.27 Å3/Da / Density % sol: 45.83 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 100mM MES, 12% PEG 4000, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: A1 / Wavelength: 0.9778 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 4, 2006
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9778 Å / Relative weight: 1
ReflectionResolution: 1.87→50 Å / Num. all: 38912 / Num. obs: 38912 / % possible obs: 90.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 1.87→1.94 Å / % possible all: 64.3

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
MOLREPphasing
PHENIX(phenix.refine: 1.6_289)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PGJ

2pgj


Resolution: 1.878→25.246 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.25 / σ(F): 1.97 / Phase error: 27.4 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2416 1948 5.01 %RANDOM
Rwork0.1858 ---
all0.1886 38873 --
obs0.1886 38873 89.1 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 60.098 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso max: 167.58 Å2 / Biso mean: 47.2435 Å2 / Biso min: 9.54 Å2
Baniso -1Baniso -2Baniso -3
1--9.9843 Å2-0.2757 Å21.571 Å2
2---0.7623 Å2-7.141 Å2
3---10.7467 Å2
Refinement stepCycle: LAST / Resolution: 1.878→25.246 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4032 0 72 251 4355
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074223
X-RAY DIFFRACTIONf_angle_d1.1255724
X-RAY DIFFRACTIONf_chiral_restr0.072618
X-RAY DIFFRACTIONf_plane_restr0.004726
X-RAY DIFFRACTIONf_dihedral_angle_d20.9021564
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8777-1.92460.3575830.24781391147447
1.9246-1.97660.27481000.22442058215869
1.9766-2.03480.30831150.21282259237477
2.0348-2.10040.27161320.21432461259383
2.1004-2.17550.26181330.19842684281790
2.1755-2.26250.24921530.1942780293394
2.2625-2.36540.25151330.19262864299797
2.3654-2.490.26031730.18792902307598
2.49-2.64590.21151570.18172877303498
2.6459-2.84990.27621440.1882939308398
2.8499-3.13620.26291510.18452913306499
3.1362-3.58890.20711680.17422914308299
3.5889-4.51740.19721570.15512939309699
4.5174-25.24790.23031490.17972944309399
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)
12.59450.72360.34811.4410.41750.850.2309-0.0378-0.95460.0772-0.0333-0.22450.13290.0081-0.11180.1388-0.0085-0.06110.07070.05090.3978-1.1939-13.54764.3522
20.68640.6953-0.00481.67850.41380.22090.07280.0332-0.2455-0.11760.004-0.27090.0969-0.0094-0.06360.17480.03210.01420.07830.02910.10829.04933.1432-3.4854
32.3966-0.68070.02450.74120.33670.42510.21820.0593-0.8379-0.0069-0.12580.21790.0232-0.0695-0.06260.1383-0.001-0.0410.06920.01150.3265-9.1828-9.6914-0.2796
41.3225-0.0343-0.20621.22060.69130.62070.06130.07540.088-0.0745-0.14980.14420.0346-0.12050.0930.1260.0036-0.00350.11680.00490.1060.7310.65471.0198
51.00620.51130.25880.3744-0.04060.50410.2926-0.37391.05080.1117-0.1950.2839-0.3879-0.4269-0.04760.19140.1674-0.0592-0.00720.17980.1585-0.575620.6396-2.0826
61.8399-0.59650.12060.93390.61390.62780.0370.81560.1341-0.4676-0.0687-0.4828-0.01220.3251-0.02930.39110.01930.1550.43120.1110.199116.265111.616-14.6477
72.0166-0.1896-1.55520.8252-0.18122.44180.395-0.79280.92640.0752-0.07960.2466-0.31390.4695-0.33130.1736-0.14050.13820.4078-0.32340.4407-19.94122.773322.0216
82.09920.5745-0.71320.4762-0.48620.51240.5643-0.76450.07670.5826-0.20540.15730.02731.6548-0.2910.3928-0.11250.02841.1123-0.30450.0467-22.78259.002637.8183
93.85211.0369-1.16280.59530.0571.04330.31-0.76080.4681-0.0074-0.06130.11080.01380.3368-0.19410.1205-0.00540.01980.2626-0.10160.2062-18.27514.455216.5636
101.580.8261-0.52741.6254-0.75920.48830.2449-0.8662-0.10040.0942-0.6543-0.29590.15091.13230.20880.3470.0097-0.04781.3207-0.04190.1023-12.6586-1.025936.3922
110.5808-0.0394-0.72460.0465-0.28893.196-0.14670.6775-0.14690.0594-0.04290.3879-0.17990.94510.06390.44720.05170.11040.9713-0.23920.2748-30.5556-1.737446.5876
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain A and (resseq 48:117)A48 - 117
2X-RAY DIFFRACTION2chain A and (resseq 118:146)A118 - 146
3X-RAY DIFFRACTION3chain A and (resseq 147:193)A147 - 193
4X-RAY DIFFRACTION4chain A and (resseq 194:244)A194 - 244
5X-RAY DIFFRACTION5chain A and (resseq 250:275)A250 - 275
6X-RAY DIFFRACTION6chain A and (resseq 276:296)A276 - 296
7X-RAY DIFFRACTION7chain B and (resseq 48:117)B48 - 117
8X-RAY DIFFRACTION8chain B and (resseq 118:146)B118 - 146
9X-RAY DIFFRACTION9chain B and (resseq 147:193)B147 - 193
10X-RAY DIFFRACTION10chain B and (resseq 194:275)B194 - 275
11X-RAY DIFFRACTION11chain B and (resseq 276:296)B276 - 296

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