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- PDB-5uoy: Crystal structure of human PDE1B catalytic domain in complex with... -

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Basic information

Entry
Database: PDB / ID: 5uoy
TitleCrystal structure of human PDE1B catalytic domain in complex with inhibitor 16j (6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one)
ComponentsCalcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B
KeywordsHYDROLASE/HYDROLASE INHIBITOR / hydrolase / hydrolase inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


calmodulin-activated dual specificity 3',5'-cyclic-GMP, 3',5'-cyclic-AMP phosphodiesterase activity / calmodulin-activated 3',5'-cyclic-GMP phosphodiesterase activity / regulation of neurotransmitter levels / cellular response to macrophage colony-stimulating factor stimulus / regulation of dopamine metabolic process / serotonin metabolic process / 3',5'-cyclic-nucleotide phosphodiesterase / Cam-PDE 1 activation / cGMP effects / cellular response to granulocyte macrophage colony-stimulating factor stimulus ...calmodulin-activated dual specificity 3',5'-cyclic-GMP, 3',5'-cyclic-AMP phosphodiesterase activity / calmodulin-activated 3',5'-cyclic-GMP phosphodiesterase activity / regulation of neurotransmitter levels / cellular response to macrophage colony-stimulating factor stimulus / regulation of dopamine metabolic process / serotonin metabolic process / 3',5'-cyclic-nucleotide phosphodiesterase / Cam-PDE 1 activation / cGMP effects / cellular response to granulocyte macrophage colony-stimulating factor stimulus / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase activity / monocyte differentiation / response to amphetamine / locomotory behavior / visual learning / G alpha (s) signalling events / calmodulin binding / neuronal cell body / signal transduction / metal ion binding / cytosol
Similarity search - Function
3'5'-cyclic nucleotide phosphodiesterase N-terminal / 3'5'-cyclic nucleotide phosphodiesterase N-terminal / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase domain signature. ...3'5'-cyclic nucleotide phosphodiesterase N-terminal / 3'5'-cyclic nucleotide phosphodiesterase N-terminal / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-8HM / Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsCedervall, E.P. / Allerston, C.K. / Xu, R. / Sridhar, V. / Barker, R. / Aertgeerts, K.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.
Authors: Dyck, B. / Branstetter, B. / Gharbaoui, T. / Hudson, A.R. / Breitenbucher, J.G. / Gomez, L. / Botrous, I. / Marrone, T. / Barido, R. / Allerston, C.K. / Cedervall, E.P. / Xu, R. / Sridhar, V. ...Authors: Dyck, B. / Branstetter, B. / Gharbaoui, T. / Hudson, A.R. / Breitenbucher, J.G. / Gomez, L. / Botrous, I. / Marrone, T. / Barido, R. / Allerston, C.K. / Cedervall, E.P. / Xu, R. / Sridhar, V. / Barker, R. / Aertgeerts, K. / Schmelzer, K. / Neul, D. / Lee, D. / Massari, M.E. / Andersen, C.B. / Sebring, K. / Zhou, X. / Petroski, R. / Limberis, J. / Augustin, M. / Chun, L.E. / Edwards, T.E. / Peters, M. / Tabatabaei, A.
History
DepositionFeb 1, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 26, 2017Provider: repository / Type: Initial release
Revision 1.1May 10, 2017Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,3005
Polymers41,2791
Non-polymers1,0214
Water2,522140
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area240 Å2
ΔGint-49 kcal/mol
Surface area14690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.507, 87.507, 134.714
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B / Cam-PDE 1B / 63 kDa Cam-PDE


Mass: 41279.035 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE1B, PDE1B1, PDES1B / Production host: Escherichia coli (E. coli)
References: UniProt: Q01064, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-8HM / 6-[(4-methoxyphenyl)methyl]-9-[(oxan-4-yl)methyl]-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one


Mass: 465.568 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H27N5O3S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 140 / 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: 3.12 Å3/Da / Density % sol: 60.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.9 / Details: 3.1 M NaCl, 0.1 M HEPES pH 6.9

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 4, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.82→61.88 Å / Num. obs: 47503 / % possible obs: 99.8 % / Redundancy: 10.4 % / Biso Wilson estimate: 30.53 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.023 / Rrim(I) all: 0.075 / Net I/σ(I): 14.1
Reflection shellResolution: 1.82→1.87 Å / Redundancy: 9.7 % / Rmerge(I) obs: 1.932 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 3451 / CC1/2: 0.489 / Rpim(I) all: 0.651 / Rrim(I) all: 2.043 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1TAZ
Resolution: 1.82→61.877 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 25.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2209 2285 4.87 %
Rwork0.1891 --
obs0.1906 46918 98.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.82→61.877 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2597 0 68 140 2805
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082730
X-RAY DIFFRACTIONf_angle_d1.0143705
X-RAY DIFFRACTIONf_dihedral_angle_d14.198962
X-RAY DIFFRACTIONf_chiral_restr0.042418
X-RAY DIFFRACTIONf_plane_restr0.005472
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.82-1.85960.42311240.40332660X-RAY DIFFRACTION96
1.8596-1.90280.41751280.38492701X-RAY DIFFRACTION95
1.9028-1.95040.44491500.34782688X-RAY DIFFRACTION98
1.9504-2.00320.31251520.28382731X-RAY DIFFRACTION99
2.0032-2.06210.27631320.25682797X-RAY DIFFRACTION99
2.0621-2.12870.25331620.23822758X-RAY DIFFRACTION99
2.1287-2.20480.23241530.21652758X-RAY DIFFRACTION99
2.2048-2.2930.27691310.22952721X-RAY DIFFRACTION97
2.293-2.39740.21261530.18712778X-RAY DIFFRACTION99
2.3974-2.52380.24491200.17892832X-RAY DIFFRACTION99
2.5238-2.68190.17521500.18432790X-RAY DIFFRACTION99
2.6819-2.8890.26041390.1812807X-RAY DIFFRACTION99
2.889-3.17970.21091520.18142804X-RAY DIFFRACTION98
3.1797-3.63980.21421250.16842894X-RAY DIFFRACTION99
3.6398-4.58550.19241490.14912870X-RAY DIFFRACTION99
4.5855-61.91250.17321650.16293044X-RAY DIFFRACTION99
Refinement TLS params.

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

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
12.1153-0.0614-0.25454.7689-0.14091.84430.2620.73160.5063-0.7407-0.09950.3896-0.4231-0.5028-0.15940.4880.1329-0.02290.51640.15590.351-28.70071.1317-28.9283
21.114-0.2043-0.5321.810.36412.43450.12530.1390.2401-0.1827-0.00910.2144-0.4336-0.3878-0.1160.3040.0781-0.01040.23840.0830.2706-28.2885-1.5147-15.0951
31.9571-0.21150.39141.2855-0.87053.29140.0508-0.0527-0.1138-0.1613-0.0411-0.23380.31340.3585-0.00470.27350.0587-0.00570.23590.0190.2804-10.0304-15.5452-9.3938
42.4311-2.0555-0.63183.56240.13861.298-0.0959-0.17520.29340.34860.1699-0.1443-0.32940.0204-0.07260.30580.0455-0.00730.22930.03780.2641-19.9844-0.9181-3.861
51.4267-0.27090.31173.00461.16332.5947-0.0523-0.0531-0.23480.2943-0.01330.40390.5083-0.33570.03540.2845-0.02620.00920.26610.05650.3118-30.981-17.289-10.0186
62.0107-3.24045.62012.8054-1.77524.71480.39731.29590.3072-0.4323-0.3365-0.33850.21721.1291-0.10640.43610.0540.09170.50470.00670.2818-12.7137-15.684-27.8405
70.93550.67920.7291.73340.42292.4779-0.14630.2518-0.5357-0.17550.1941-0.44740.58440.5552-0.05060.52470.09390.01960.3642-0.06490.4367-13.2159-25.3906-26.1809
85.7403-0.6016-2.9573.18031.00346.0605-0.02351.036-0.3613-0.5367-0.13770.54260.2415-1.12590.18040.4513-0.0871-0.15330.4857-0.02410.394-34.9203-20.9355-27.3802
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 150 through 178 )
2X-RAY DIFFRACTION2chain 'A' and (resid 179 through 262 )
3X-RAY DIFFRACTION3chain 'A' and (resid 263 through 290 )
4X-RAY DIFFRACTION4chain 'A' and (resid 291 through 316 )
5X-RAY DIFFRACTION5chain 'A' and (resid 317 through 377 )
6X-RAY DIFFRACTION6chain 'A' and (resid 378 through 401 )
7X-RAY DIFFRACTION7chain 'A' and (resid 402 through 428 )
8X-RAY DIFFRACTION8chain 'A' and (resid 429 through 501 )

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