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- PDB-5u7i: PDE2 catalytic domain complexed with inhibitors -

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Basic information

Entry
Database: PDB / ID: 5u7i
TitlePDE2 catalytic domain complexed with inhibitors
ComponentscGMP-dependent 3',5'-cyclic phosphodiesterase
KeywordsHydrolase/Hydrolase Inhibitor / PDE2 / SBDD / inhibitor / phosphodiesterase / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


regulation of cGMP-mediated signaling / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / cellular response to macrophage colony-stimulating factor stimulus / cellular response to cGMP / negative regulation of cAMP-mediated signaling / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / heart valve development / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability ...regulation of cGMP-mediated signaling / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / cellular response to macrophage colony-stimulating factor stimulus / cellular response to cGMP / negative regulation of cAMP-mediated signaling / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / heart valve development / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / regulation of mitochondrion organization / establishment of endothelial barrier / aorta development / ventricular septum development / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP-mediated signaling / TPR domain binding / cGMP catabolic process / phosphate ion binding / cGMP effects / monocyte differentiation / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / regulation of cAMP-mediated signaling / cAMP binding / cellular response to cAMP / cellular response to transforming growth factor beta stimulus / cAMP-mediated signaling / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / synaptic membrane / positive regulation of inflammatory response / cellular response to mechanical stimulus / cellular response to xenobiotic stimulus / presynaptic membrane / G alpha (s) signalling events / mitochondrial outer membrane / mitochondrial inner membrane / mitochondrial matrix / positive regulation of gene expression / perinuclear region of cytoplasm / Golgi apparatus / negative regulation of transcription by RNA polymerase II / magnesium ion binding / endoplasmic reticulum / protein homodimerization activity / zinc ion binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
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. / GAF domain ...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. / GAF domain / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-7XS / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsPandit, J.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor.
Authors: Helal, C.J. / Arnold, E.P. / Boyden, T.L. / Chang, C. / Chappie, T.A. / Fennell, K.F. / Forman, M.D. / Hajos, M. / Harms, J.F. / Hoffman, W.E. / Humphrey, J.M. / Kang, Z. / Kleiman, R.J. / ...Authors: Helal, C.J. / Arnold, E.P. / Boyden, T.L. / Chang, C. / Chappie, T.A. / Fennell, K.F. / Forman, M.D. / Hajos, M. / Harms, J.F. / Hoffman, W.E. / Humphrey, J.M. / Kang, Z. / Kleiman, R.J. / Kormos, B.L. / Lee, C.W. / Lu, J. / Maklad, N. / McDowell, L. / Mente, S. / O'Connor, R.E. / Pandit, J. / Piotrowski, M. / Schmidt, A.W. / Schmidt, C.J. / Ueno, H. / Verhoest, P.R. / Yang, E.X.
History
DepositionDec 12, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
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_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_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: cGMP-dependent 3',5'-cyclic phosphodiesterase
B: cGMP-dependent 3',5'-cyclic phosphodiesterase
C: cGMP-dependent 3',5'-cyclic phosphodiesterase
D: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)162,72916
Polymers160,9004
Non-polymers1,82912
Water15,367853
1
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6824
Polymers40,2251
Non-polymers4573
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6824
Polymers40,2251
Non-polymers4573
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6824
Polymers40,2251
Non-polymers4573
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6824
Polymers40,2251
Non-polymers4573
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.780, 72.940, 91.000
Angle α, β, γ (deg.)109.200, 89.390, 88.900
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
cGMP-dependent 3',5'-cyclic phosphodiesterase / Cyclic GMP-stimulated phosphodiesterase / cGSPDE


Mass: 40225.102 Da / Num. of mol.: 4 / Fragment: Catalytic domain of PDE2, UNP residues 323-663
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE2A / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf21
References: UniProt: O00408, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical
ChemComp-7XS / 4-[3-(4-methoxyphenoxy)azetidin-1-yl]-1-methyl-3-(2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidine


Mass: 367.445 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H25N5O2
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 853 / 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: 2.17 Å3/Da / Density % sol: 43.38 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / Details: 25% PEG 3350, 0.1 M Tris, pH 8.5, and 0.2 M MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 9, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 88454 / % possible obs: 97.1 % / Redundancy: 3.6 % / Biso Wilson estimate: 22.73 Å2 / Rmerge(I) obs: 0.053 / Χ2: 1.241 / Net I/σ(I): 15.1 / Num. measured all: 314700
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2-2.073.40.12587081.065195.3
2.07-2.153.60.187831.024196.8
2.15-2.253.50.09487871.208197.2
2.25-2.373.60.08189071.198197.5
2.37-2.523.70.0789331.264197.6
2.52-2.713.60.06389041.392198.1
2.71-2.993.60.05689681.345198.3
2.99-3.423.70.04889691.455198.6
3.42-4.313.60.04389851.251198.4
4.31-503.40.0485101.163193.5

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
BUSTER2.11.5refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
HKL-2000data reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ITU

3itu


Resolution: 2→34.33 Å / Cor.coef. Fo:Fc: 0.9276 / Cor.coef. Fo:Fc free: 0.9076 / SU R Cruickshank DPI: 0.21 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.21 / SU Rfree Blow DPI: 0.162 / SU Rfree Cruickshank DPI: 0.163
RfactorNum. reflection% reflectionSelection details
Rfree0.2214 4424 5.01 %RANDOM
Rwork0.1938 ---
obs0.1952 88361 96.6 %-
Displacement parametersBiso max: 107.55 Å2 / Biso mean: 27.34 Å2 / Biso min: 3.02 Å2
Baniso -1Baniso -2Baniso -3
1-1.9291 Å2-0.3062 Å2-3.5654 Å2
2--0.311 Å20.9507 Å2
3----2.2402 Å2
Refine analyzeLuzzati coordinate error obs: 0.259 Å
Refinement stepCycle: final / Resolution: 2→34.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10843 0 216 853 11912
Biso mean--28.93 31.48 -
Num. residues----1325
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4010SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes274HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1724HARMONIC5
X-RAY DIFFRACTIONt_it11342HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1431SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact14068SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d11342HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg15401HARMONIC20.9
X-RAY DIFFRACTIONt_omega_torsion2.69
X-RAY DIFFRACTIONt_other_torsion17.02
LS refinement shellResolution: 2→2.05 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2824 297 4.98 %
Rwork0.2385 5670 -
all0.2408 5967 -
obs--96.6 %
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)
11.4723-0.0038-0.42420.53380.21861.2497-0.02190.172-0.0647-0.04880.00020.04390.0455-0.01790.0217-0.0399-0.02840.002-0.0394-0.0042-0.051.2949-0.3342-0.8661
21.2471-0.1491-0.28550.68540.14211.3150.0081-0.12750.03270.04420.0362-0.04810.01190.0247-0.0443-0.0548-0.0259-0.0118-0.0201-0.0119-0.060118.75642.453538.5082
31.49460.12360.05780.6321-0.13861.50850.0767-0.18540.02950.0928-0.0529-0.12270.00990.0401-0.0238-0.0981-0.0299-0.0148-0.0121-0.0359-0.042345.243235.995637.7038
41.22520.0988-0.44260.60590.16411.10450.04290.22020.153-0.07770.01960.0863-0.0687-0.1616-0.0625-0.0879-0.0131-0.00360.01950.0388-0.028628.522533.1284-3.0738
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A579 - 916
2X-RAY DIFFRACTION2{ B|* }B580 - 915
3X-RAY DIFFRACTION3{ C|* }C590 - 916
4X-RAY DIFFRACTION4{ D|* }D590 - 913

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