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- PDB-5u7l: PDE2 catalytic domain complexed with inhibitors -

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Basic information

Entry
Database: PDB / ID: 5u7l
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 / 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 / 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-7Y4 / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 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 1.2Oct 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 / refine_hist / struct_conn / struct_ncs_dom_lim
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 / _refine_hist.d_res_low / _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 / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,23612
Polymers120,6753
Non-polymers1,5619
Water3,261181
1
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7454
Polymers40,2251
Non-polymers5203
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)40,7454
Polymers40,2251
Non-polymers5203
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)40,7454
Polymers40,2251
Non-polymers5203
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)168.021, 73.922, 92.136
Angle α, β, γ (deg.)90.000, 109.510, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31C

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: ILE / Beg label comp-ID: ILE / End auth comp-ID: SER / End label comp-ID: SER / Refine code: 4 / Auth seq-ID: 590 - 899 / Label seq-ID: 16 - 325

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB
3CC

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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.: 3 / 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-7Y4 / (3R)-1-{3-[5-(4-ethylphenyl)-1-methyl-1H-pyrazol-4-yl]-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-N,N-dimethylpyrrolidin-3-amine


Mass: 430.549 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C24H30N8
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 181 / 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: 2.23 Å3/Da / Density % sol: 44.96 %
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: 21-ID-D / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Apr 2, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.38→44 Å / Num. obs: 39566 / % possible obs: 93.2 % / Redundancy: 2.7 % / Rmerge(I) obs: 0.097 / Χ2: 1.748 / Net I/σ(I): 10.1 / Num. measured all: 107997
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.38-2.441.50.36214971.222171.4
2.44-2.491.60.40216501.001177.4
2.49-2.531.80.40917021.242180.8
2.53-2.5920.40618081.196185.7
2.59-2.642.20.33318531.034187.9
2.64-2.72.30.33619001.152190.4
2.7-2.772.50.29819631.213192.9
2.77-2.852.70.28720011.18194.8
2.85-2.932.80.25320001.267196.4
2.93-3.0230.24621011.283197.6
3.02-3.133.10.19720851.372199.1
3.13-3.263.10.15821211.467199.5
3.26-3.413.20.13121221.694199.6
3.41-3.583.10.11220952.013199.5
3.58-3.813.10.08421072.251199.3
3.81-4.13.10.06821092.295199.1
4.1-4.523.10.05320982.384198.1
4.52-5.173.10.04920932.574197.7
5.17-6.513.10.04921162.251198.4
6.51-4430.03621452.131197.1

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
REFMAC5.4.0069refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
HKL-2000data reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ITU

3itu


Resolution: 2.38→43 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.884 / WRfactor Rfree: 0.2572 / WRfactor Rwork: 0.1931 / FOM work R set: 0.7836 / SU B: 10.156 / SU ML: 0.235 / SU R Cruickshank DPI: 0.7495 / SU Rfree: 0.3308 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.749 / ESU R Free: 0.331 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2813 1999 5.1 %RANDOM
Rwork0.2085 ---
obs0.2122 37520 92.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 69.52 Å2 / Biso mean: 32.379 Å2 / Biso min: 6.07 Å2
Baniso -1Baniso -2Baniso -3
1--2.48 Å20 Å2-1.65 Å2
2--1.18 Å20 Å2
3---0.2 Å2
Refinement stepCycle: final / Resolution: 2.38→43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8093 0 115 168 8376
Biso mean--24 32.74 -
Num. residues----987
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0218397
X-RAY DIFFRACTIONr_angle_refined_deg1.6341.96211341
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8365983
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.84223.765417
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.355151497
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9921551
X-RAY DIFFRACTIONr_chiral_restr0.1010.21206
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0216481
Refine LS restraints NCS

Ens-ID: 1 / Number: 2405 / Refine-ID: X-RAY DIFFRACTION

Dom-IDAuth asym-IDTypeRms dev position (Å)Weight position
1AMEDIUM POSITIONAL0.350.5
2BMEDIUM POSITIONAL0.460.5
3CMEDIUM POSITIONAL0.50.5
1AMEDIUM THERMAL0.852
2BMEDIUM THERMAL1.152
3CMEDIUM THERMAL1.022
LS refinement shellResolution: 2.384→2.446 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 100 -
Rwork0.271 1958 -
all-2058 -
obs--66.09 %

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