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- PDB-4c1i: Selective Inhibitors of PDE2, PDE9, and PDE10: Modulators of Acti... -

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Basic information

Entry
Database: PDB / ID: 4c1i
TitleSelective Inhibitors of PDE2, PDE9, and PDE10: Modulators of Activity of the Central Nervous System
ComponentsCGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
KeywordsHYDROLASE / 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 / heart valve development / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of vascular permeability / 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 / heart valve development / cellular response to granulocyte macrophage colony-stimulating factor stimulus / positive regulation of vascular permeability / negative regulation of vascular permeability / establishment of endothelial barrier / regulation of mitochondrion organization / aorta development / ventricular septum development / cGMP-mediated signaling / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / phosphate ion binding / cGMP effects / TPR domain binding / monocyte differentiation / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling / cAMP binding / cellular response to transforming growth factor beta stimulus / cellular response to cAMP / synaptic membrane / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cellular response to mechanical stimulus / positive regulation of inflammatory response / 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 / negative regulation of transcription by RNA polymerase II / magnesium ion binding / endoplasmic reticulum / Golgi apparatus / 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 / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / GAF-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
(2S,3R)-3-(6-amino-9H-purin-9-yl)nonan-2-ol / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsJorgensen, M. / Kehler, J. / Langgard, M. / Svenstrup, N. / Tagmose, L.
CitationJournal: To be Published
Title: Chapter 4: Selective Inhibitors of Pde2, Pde9, and Pde10: Modulators of Activity of the Central Nervous System
Authors: Jorgensen, M. / Kehler, J. / Langgard, M. / Svenstrup, N. / Tagmose, L.
History
DepositionAug 12, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 27, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_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_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_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
D: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)167,19816
Polymers165,7304
Non-polymers1,46812
Water4,468248
1
A: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,7994
Polymers41,4321
Non-polymers3673
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)41,7994
Polymers41,4321
Non-polymers3673
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)41,7994
Polymers41,4321
Non-polymers3673
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)41,7994
Polymers41,4321
Non-polymers3673
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.050, 81.810, 93.340
Angle α, β, γ (deg.)110.16, 95.66, 93.21
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 / CGS-PDE / CGSPDE


Mass: 41432.375 Da / Num. of mol.: 4 / Fragment: CATALYTIC DOMAIN, RESIDUES 578-921
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O00408, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical
ChemComp-EH9 / (2S,3R)-3-(6-amino-9H-purin-9-yl)nonan-2-ol / Erythro-9-[3-(2-hydroxynonyl)] adenine / EHNA


Mass: 277.365 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H23N5O / Comment: inhibitor*YM
#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.: 248 / 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 Å3/Da / Density % sol: 39 % / Description: NONE
Crystal growpH: 8.6
Details: 14% PEG 3350, 0.2 M MAGNESIUM CHLORIDE, 0.1 M TRIS HYDROCHLORIDE PH 8.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD / Date: Jun 12, 2008 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→18.47 Å / Num. obs: 47638 / % possible obs: 94.1 % / Observed criterion σ(I): 2 / Redundancy: 2 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 7.1
Reflection shellResolution: 2.4→2.48 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.31 / Mean I/σ(I) obs: 2 / % possible all: 91.5

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1Z1L

1z1l


Resolution: 2.4→18.47 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.872 / SU B: 11.146 / SU ML: 0.257 / Cross valid method: THROUGHOUT / ESU R: 1.166 / ESU R Free: 0.347 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2866 2434 5.1 %RANDOM
Rwork0.22489 ---
obs0.22801 45148 93.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.988 Å2
Baniso -1Baniso -2Baniso -3
1-3.42 Å2-1.88 Å2-0.59 Å2
2---0.42 Å20.06 Å2
3----2.16 Å2
Refinement stepCycle: LAST / Resolution: 2.4→18.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10334 0 88 248 10670
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.01910714
X-RAY DIFFRACTIONr_bond_other_d0.0010.029906
X-RAY DIFFRACTIONr_angle_refined_deg0.9071.9514436
X-RAY DIFFRACTIONr_angle_other_deg0.7213.00222602
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.80251279
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.64123.743521
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.294151813
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3141561
X-RAY DIFFRACTIONr_chiral_restr0.050.21571
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212041
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022608
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.823.0485128
X-RAY DIFFRACTIONr_mcbond_other0.823.0475127
X-RAY DIFFRACTIONr_mcangle_it1.4374.5676403
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.7113.085586
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.386 175 -
Rwork0.295 3268 -
obs--90.89 %

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