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- PDB-5up0: Crystal structure of human PDE1B catalytic domain in complex with... -

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Basic information

Entry
Database: PDB / ID: 5up0
TitleCrystal structure of human PDE1B catalytic domain in complex with inhibitor 3 (6-(4-chlorobenzyl)-8,9,10,11-tetrahydrobenzo[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 / cellular response to macrophage colony-stimulating factor stimulus / serotonin metabolic process / dopamine catabolic process / cellular response to granulocyte macrophage colony-stimulating factor stimulus / Cam-PDE 1 activation / 3',5'-cyclic-nucleotide phosphodiesterase / cGMP effects / monocyte differentiation ...calmodulin-activated dual specificity 3',5'-cyclic-GMP, 3',5'-cyclic-AMP phosphodiesterase activity / calmodulin-activated 3',5'-cyclic-GMP phosphodiesterase activity / cellular response to macrophage colony-stimulating factor stimulus / serotonin metabolic process / dopamine catabolic process / cellular response to granulocyte macrophage colony-stimulating factor stimulus / Cam-PDE 1 activation / 3',5'-cyclic-nucleotide phosphodiesterase / cGMP effects / monocyte differentiation / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / response to amphetamine / cAMP-mediated signaling / locomotory behavior / visual learning / G alpha (s) signalling events / calmodulin binding / neuronal cell body / metal ion binding / cytosol
Similarity search - Function
3'5'-cyclic nucleotide phosphodiesterase N-terminal / 3'5'-cyclic nucleotide phosphodiesterase N-terminal / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. ...3'5'-cyclic nucleotide phosphodiesterase N-terminal / 3'5'-cyclic nucleotide phosphodiesterase N-terminal / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 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-8HP / 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: 2.04 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
Revision 1.2Oct 4, 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)41,7404
Polymers41,2791
Non-polymers4613
Water1,892105
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area240 Å2
ΔGint-49 kcal/mol
Surface area14820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.381, 87.381, 135.088
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: isolated from a genetically manipulated source
Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: Mg
#4: Chemical ChemComp-8HP / 6-[(4-chlorophenyl)methyl]-8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one


Mass: 370.856 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H15ClN4OS
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 105 / 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: 60.55 %
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: 2.04→61.79 Å / Num. obs: 34119 / % possible obs: 100 % / Redundancy: 10.3 % / Biso Wilson estimate: 37.05 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.073 / Rpim(I) all: 0.024 / Rrim(I) all: 0.077 / Net I/σ(I): 14.2
Reflection shellResolution: 2.04→2.09 Å / Redundancy: 10.5 % / Rmerge(I) obs: 1.626 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 2482 / CC1/2: 0.653 / Rpim(I) all: 0.525 / Rrim(I) all: 1.71 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1TAZ

1taz


Resolution: 2.04→61.788 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 27.23 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2262 1671 5.01 %Random selection
Rwork0.197 ---
obs0.1985 33382 98.03 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.04→61.788 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2597 0 27 105 2729
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082683
X-RAY DIFFRACTIONf_angle_d1.0613638
X-RAY DIFFRACTIONf_dihedral_angle_d15.225960
X-RAY DIFFRACTIONf_chiral_restr0.045416
X-RAY DIFFRACTIONf_plane_restr0.005462
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.04-2.10.40641260.35312612X-RAY DIFFRACTION98
2.1-2.16780.32441330.33362625X-RAY DIFFRACTION99
2.1678-2.24530.32521360.32552554X-RAY DIFFRACTION97
2.2453-2.33520.36661460.29062555X-RAY DIFFRACTION97
2.3352-2.44150.3011420.2352618X-RAY DIFFRACTION99
2.4415-2.57020.24061240.23342619X-RAY DIFFRACTION98
2.5702-2.73130.23431460.21612626X-RAY DIFFRACTION98
2.7313-2.94210.23131350.20442614X-RAY DIFFRACTION98
2.9421-3.23820.24991330.1992656X-RAY DIFFRACTION98
3.2382-3.70670.21171430.17322647X-RAY DIFFRACTION98
3.7067-4.66980.17621490.15082692X-RAY DIFFRACTION98
4.6698-61.8160.18491580.16572893X-RAY DIFFRACTION99
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)
10.6892-0.75930.12412.9322-0.18360.7530.23080.63070.4559-0.692-0.09390.1358-0.2335-0.2649-0.11860.60690.1369-0.01830.54890.19460.462-28.69180.8789-28.9846
20.65870.0369-0.27751.90840.16692.7010.13120.1120.2938-0.1637-0.02350.1281-0.5251-0.2747-0.10650.4280.07890.00710.28320.11090.3776-26.492-0.5612-16.5258
30.8068-0.0710.061.4222-0.19362.06430.02880.0021-0.0014-0.03910.04790.04150.0639-0.0159-0.07050.31060.0403-0.01530.25440.06580.3134-20.038-11.9522-9.7741
41.8137-1.2663-0.3362.36550.03291.2684-0.1533-0.1450.33950.43030.1501-0.1556-0.32050.1077-0.00170.40380.0603-0.00130.31070.07560.3807-20.1284-1.1464-3.9608
51.1743-0.0006-0.20461.64350.20341.4105-0.163-0.0613-0.2180.2290.12650.36830.5171-0.13680.02190.36690.00270.03270.27110.09150.3529-29.4642-17.12-6.5553
63.2597-0.3014-0.58351.98640.7143.1702-0.1643-0.0808-0.30640.0292-0.02790.43850.168-0.32340.09870.2597-0.0074-0.03030.25120.05650.3765-33.4596-17.9061-14.6564
75.2452-1.41212.2122.232-0.55183.36550.56151.10380.2694-0.5838-0.3747-0.30670.43420.7858-0.0760.6010.05820.09020.45990.0350.3081-12.6625-15.7615-27.8376
80.02890.0125-0.21841.35240.60431.9401-0.15140.3485-0.7346-0.30060.1146-0.34810.65570.5620.12650.66210.10160.08550.4518-0.02910.4366-13.1877-25.4047-26.48
93.6385-0.8066-1.382.67080.64473.94970.03620.8772-0.5829-0.5476-0.22030.52070.1871-1.15530.11680.4952-0.0877-0.14720.6094-0.04880.4583-34.9573-21.2376-27.4175
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 242 )
3X-RAY DIFFRACTION3chain 'A' and (resid 243 through 290 )
4X-RAY DIFFRACTION4chain 'A' and (resid 291 through 316 )
5X-RAY DIFFRACTION5chain 'A' and (resid 317 through 351 )
6X-RAY DIFFRACTION6chain 'A' and (resid 352 through 377 )
7X-RAY DIFFRACTION7chain 'A' and (resid 378 through 401 )
8X-RAY DIFFRACTION8chain 'A' and (resid 402 through 428 )
9X-RAY DIFFRACTION9chain 'A' and (resid 429 through 501 )

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