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- PDB-3u4i: CD38 structure-based inhibitor design using the N1-cyclic inosine... -

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Basic information

Entry
Database: PDB / ID: 3u4i
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 / cADPcR / HYDROLASE-HYDROLASE INHIBITOR complex
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 / NAD metabolic process / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / 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 / 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
Cyclic adenosine 5'-diphosphocarbocyclic ribose / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.118 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)61,3003
Polymers60,7612
Non-polymers5391
Water2,666148
1
A: ADP-ribosyl cyclase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,9202
Polymers30,3801
Non-polymers5391
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: ADP-ribosyl cyclase 1


Theoretical massNumber of molelcules
Total (without water)30,3801
Polymers30,3801
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.223, 53.998, 66.547
Angle α, β, γ (deg.)105.20, 91.08, 94.68
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-CVR / Cyclic adenosine 5'-diphosphocarbocyclic ribose


Mass: 539.328 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H23N5O12P2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 148 / 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: 2.4 Å3/Da / Density % sol: 48.74 %
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: Jul 14, 2007
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: 2.1→30 Å / Num. all: 30776 / Num. obs: 30776 / % possible obs: 96.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 34.38 Å2
Reflection shellResolution: 2.1→2.18 Å / % possible all: 85.6

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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: 2.118→23.434 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.29 / σ(F): 1.97 / Phase error: 22.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2172 1550 5.04 %RANDOM
Rwork0.1795 ---
all0.1815 30761 --
obs0.1815 30761 95.75 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 58.303 Å2 / ksol: 0.379 e/Å3
Displacement parametersBiso max: 167.24 Å2 / Biso mean: 52.1413 Å2 / Biso min: 16.71 Å2
Baniso -1Baniso -2Baniso -3
1--6.7822 Å22.6622 Å21.6332 Å2
2--0.1647 Å25.026 Å2
3---6.6175 Å2
Refinement stepCycle: LAST / Resolution: 2.118→23.434 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3978 0 35 148 4161
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074127
X-RAY DIFFRACTIONf_angle_d1.0515584
X-RAY DIFFRACTIONf_chiral_restr0.072606
X-RAY DIFFRACTIONf_plane_restr0.005707
X-RAY DIFFRACTIONf_dihedral_angle_d18.8581522
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1176-2.18590.29891010.21852155225679
2.1859-2.26390.22831470.19372546269391
2.2639-2.35450.22251440.18622695283996
2.3545-2.46150.23771360.18842691282797
2.4615-2.59120.23731450.18572674281998
2.5912-2.75330.23251480.18872731287998
2.7533-2.96550.25421380.19432743288198
2.9655-3.26320.24221340.18792757289199
3.2632-3.73380.20341620.17522719288199
3.7338-4.69790.17631490.14782756290599
4.6979-23.43590.20511460.16852744289099
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)
10.7642.0022-1.24435.2524-3.41436.3660.42630.36421.18460.4949-1.2514-0.1069-0.04680.09280.7190.55160.102-0.16990.98010.26660.927923.6753-18.349413.2753
22.5253-2.16811.01585.1702-1.33031.45390.13230.02-1.306-0.12290.16570.44190.1787-0.1475-0.27880.2026-0.0065-0.00850.1731-0.01860.70590.7585-15.2811-2.4671
31.757-0.3869-0.07151.289-0.63420.34180.03940.1471-0.6672-0.0025-0.02720.0629-0.06750.0268-0.02550.19830.0291-0.00840.203-0.05660.311-2.7927-1.8187-5.5088
40.55640.1211-0.73133.1258-1.95651.99750.05030.1019-0.25970.44280.31410.6532-0.2637-0.3627-0.26340.4169-0.02030.0970.33140.08440.2946-12.75422.46576.0311
51.5506-0.660.15963.6646-1.40330.8088-0.1767-0.0459-0.24360.41060.0892-0.6891-0.08580.1250.07640.25680.0297-0.03850.1697-0.01450.53728.3564-9.3370.6381
63.21250.5211-0.33864.0408-0.63350.65140.0085-0.0185-0.18510.3116-0.0279-0.10560.01090.14570.02030.22590.02250.01040.21430.02570.1577-0.584210.6623-1.4683
72.63660.8406-0.84683.35390.37250.65810.27090.04390.61690.1041-0.0996-0.1076-0.4242-0.0118-0.11330.2149-0.0242-0.03660.147-0.06350.17231.122520.95041.364
83.6185-0.3350.71270.696-0.23450.60830.4479-1.33130.48150.73460.09050.6876-0.4479-0.6847-0.27620.6580.07670.20470.6699-0.01740.3112-16.057312.690414.5781
90.82581.25060.16732.11480.08270.1692-0.231-0.2956-0.6817-0.67850.62830.2194-0.58-1.4131-0.24360.50150.3401-0.03810.70070.2130.215623.597811.98633.5778
101.54240.73820.03051.5656-0.72430.5524-0.22720.05070.0221-0.3119-0.0185-0.18610.10240.01260.1680.18530.00790.01010.26470.03440.180225.078713.7593-11.0347
112.62280.3187-0.05151.54890.12032.119-0.03580.41080.3052-0.3007-0.01190.0096-0.3486-0.12830.02750.31310.00360.00060.2760.0760.235419.082422.5269-26.1912
126.06921.970.32521.93072.60214.84020.5740.895-0.8885-0.08690.2288-0.4423-0.09650.3611-0.67160.2997-0.0306-0.04490.4408-0.06310.43224.1175.1327-37.6798
132.44371.31580.68580.96540.22540.25290.04210.28460.0105-0.14290.07940.0356-0.17270.2385-0.12320.29080.00970.01330.20010.02950.196621.268715.6714-24.1659
142.6911-0.715-1.87390.4425-0.05912.4459-0.01730.0018-0.4292-0.0259-0.12020.0780.255-0.30510.15270.1972-0.0281-0.00610.2166-0.0110.252515.943910.5719-17.2429
153.02142.98430.37663.07921.1234.3090.3844-0.0216-1.00610.3175-0.1149-0.06110.4279-0.8451-0.25530.3821-0.0399-0.11630.4834-0.03260.487713.7797-0.6543-35.5323
165.62634.86930.89384.65942.05933.79330.98140.3065-2.26370.2001-0.15720.36410.8629-0.797-0.68080.5196-0.221-0.30020.47770.00141.018111.3232-10.1676-37.5746
172.2522-3.24391.6615.0091-1.17085.60360.75821.4745-1.5717-0.3386-0.10660.12740.67442.0103-0.63950.4510.1726-0.13990.8473-0.64071.248931.2025-6.2817-42.2756
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain A and (resseq 45:49)A45 - 49
2X-RAY DIFFRACTION2chain A and (resseq 50:103)A50 - 103
3X-RAY DIFFRACTION3chain A and (resseq 104:129)A104 - 129
4X-RAY DIFFRACTION4chain A and (resseq 130:143)A130 - 143
5X-RAY DIFFRACTION5chain A and (resseq 144:193)A144 - 193
6X-RAY DIFFRACTION6chain A and (resseq 194:244)A194 - 244
7X-RAY DIFFRACTION7chain A and (resseq 250:275)A250 - 275
8X-RAY DIFFRACTION8chain A and (resseq 276:296)A276 - 296
9X-RAY DIFFRACTION9chain B and (resseq 45:48)B45 - 48
10X-RAY DIFFRACTION10chain B and (resseq 49:58)B49 - 58
11X-RAY DIFFRACTION11chain B and (resseq 59:116)B59 - 116
12X-RAY DIFFRACTION12chain B and (resseq 117:140)B117 - 140
13X-RAY DIFFRACTION13chain B and (resseq 141:167)B141 - 167
14X-RAY DIFFRACTION14chain B and (resseq 168:195)B168 - 195
15X-RAY DIFFRACTION15chain B and (resseq 196:244)B196 - 244
16X-RAY DIFFRACTION16chain B and (resseq 250:275)B250 - 275
17X-RAY DIFFRACTION17chain B and (resseq 276:289)B276 - 289

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