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- PDB-5u7j: PDE2 catalytic domain complexed with inhibitors -

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Basic information

Entry
Database: PDB / ID: 5u7j
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 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 / establishment of endothelial barrier ...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 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 / establishment of endothelial barrier / negative regulation of cAMP-mediated signaling / regulation of mitochondrion organization / aorta development / ventricular septum development / cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / TPR domain binding / cGMP-mediated signaling / 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 / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cAMP-mediated signaling / 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 / cytoplasm / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / 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-7XV / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsPandit, J. / Parris, K.
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 1.2Nov 22, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Oct 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)162,56516
Polymers160,9004
Non-polymers1,66412
Water22,4111244
1
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,6414
Polymers40,2251
Non-polymers4163
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)40,6414
Polymers40,2251
Non-polymers4163
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)40,6414
Polymers40,2251
Non-polymers4163
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)40,6414
Polymers40,2251
Non-polymers4163
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.866, 74.035, 92.411
Angle α, β, γ (deg.)109.660, 91.430, 90.920
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-7XV / 5-[2-(2-methoxyphenyl)ethoxy]-3-(2-methylpropyl)[1,2,4]triazolo[4,3-a]pyrazine


Mass: 326.393 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H22N4O2
#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.: 1244 / 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: 2.24 Å3/Da / Density % sol: 44.98 %
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: Apr 6, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.89→50 Å / Num. obs: 106624 / % possible obs: 95.9 % / Redundancy: 2 % / Biso Wilson estimate: 23.54 Å2 / Rmerge(I) obs: 0.061 / Χ2: 1.401 / Net I/σ(I): 9.4 / Num. measured all: 210202
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.89-1.961.90.44399651.653189.6
1.96-2.0420.307107041.024196.6
2.04-2.1320.218106121.415195.2
2.13-2.2420.173106651.407195.9
2.24-2.3820.128106291.445195.9
2.38-2.5720.084108251.182197.4
2.57-2.8220.066108641.28197.8
2.82-3.2320.048109041.445197.9
3.23-4.0720.036107461.741196.8
4.07-5020.027107101.458196.4

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Processing

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

3itu


Resolution: 1.9→44.18 Å / Cor.coef. Fo:Fc: 0.9411 / Cor.coef. Fo:Fc free: 0.9223 / SU R Cruickshank DPI: 0.177 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.183 / SU Rfree Blow DPI: 0.15 / SU Rfree Cruickshank DPI: 0.148
RfactorNum. reflection% reflectionSelection details
Rfree0.2246 5220 4.98 %RANDOM
Rwork0.1943 ---
obs0.1958 104828 95.46 %-
Displacement parametersBiso max: 117.87 Å2 / Biso mean: 30.15 Å2 / Biso min: 8.2 Å2
Baniso -1Baniso -2Baniso -3
1-4.1068 Å20.4159 Å2-0.2522 Å2
2---3.1972 Å2-0.839 Å2
3----0.9097 Å2
Refine analyzeLuzzati coordinate error obs: 0.287 Å
Refinement stepCycle: final / Resolution: 1.9→44.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10870 0 192 1244 12306
Biso mean--33.94 37.46 -
Num. residues----1328
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d4096SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes275HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1766HARMONIC5
X-RAY DIFFRACTIONt_it11519HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1457SEMIHARMONIC5
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_contact14758SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d11519HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg15642HARMONIC20.91
X-RAY DIFFRACTIONt_omega_torsion2.71
X-RAY DIFFRACTIONt_other_torsion17.46
LS refinement shellResolution: 1.9→1.95 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.4406 338 5.1 %
Rwork0.4366 6289 -
all0.4368 6627 -
obs--95.46 %
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)
11.2870.190.24920.81140.11920.90980.0307-0.21050.08750.051-0.03960.0188-0.0554-0.01680.0089-0.0214-0.0178-0.03940.0059-0.0403-0.04290.741-0.6010.646
21.13720.05960.06011.0070.02531.14020.03240.1087-0.0235-0.04060.03020.03060.0154-0.0129-0.0626-0.0170.0103-0.0542-0.0466-0.0344-0.024618.538-3.113-38.897
31.61020.0952-0.37360.7851-0.09531.78120.06910.0914-0.0878-0.09290.0093-0.11950.00010.1368-0.0784-0.07890.0027-0.034-0.0501-0.0939-0.018744.816-37.309-37.98
41.0931-0.15030.04080.74390.2260.85070.0135-0.1407-0.0930.0799-0.01520.05480.031-0.05680.0017-0.0366-0.018-0.05510.00910.00390.002428.389-33.6272.905
50.18010.3448-0.1552-0.24740.1741.0888-0.00680.03010.0977-0.04360.0111-0.1075-0.0442-0.0963-0.00430.0333-0.0311-0.0916-0.03180.02160.116323.1-13.017-18.469
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|579 - A|916 }A579 - 916
2X-RAY DIFFRACTION2{ B|580 - B|915 }B580 - 915
3X-RAY DIFFRACTION3{ C|590 - C|916 }C590 - 916
4X-RAY DIFFRACTION4{ D|590 - D|916 }D590 - 916
5X-RAY DIFFRACTION5{ A|1001 - A|1001 C|1001 - C|1001 B|1001 - B|1001 D|1001 - D|1001 }A1001
6X-RAY DIFFRACTION5{ A|1001 - A|1001 C|1001 - C|1001 B|1001 - B|1001 D|1001 - D|1001 }C1001
7X-RAY DIFFRACTION5{ A|1001 - A|1001 C|1001 - C|1001 B|1001 - B|1001 D|1001 - D|1001 }B1001
8X-RAY DIFFRACTION5{ A|1001 - A|1001 C|1001 - C|1001 B|1001 - B|1001 D|1001 - D|1001 }D1001

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