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- PDB-5xkm: Crystal structure of human phosphodiesterase 2A in complex with 6... -

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Basic information

Entry
Database: PDB / ID: 5xkm
TitleCrystal structure of human phosphodiesterase 2A in complex with 6-methyl-N-(1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
ComponentscGMP-dependent 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE / Hydrolase Inhibitor / PDE2A
Function / homology
Function and homology information


: / 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 / positive regulation of vascular permeability / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / establishment of endothelial barrier ...: / 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 / positive regulation of vascular permeability / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / establishment of endothelial barrier / regulation of mitochondrion organization / : / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / aorta development / ventricular septum development / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cGMP effects / phosphate ion binding / TPR domain binding / cGMP binding / monocyte differentiation / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cellular response to transforming growth factor beta stimulus / : / cAMP binding / synaptic membrane / cellular response to cAMP / cellular response to mechanical stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cellular response to xenobiotic stimulus / positive regulation of inflammatory response / presynaptic membrane / G alpha (s) signalling events / mitochondrial outer membrane / mitochondrial inner membrane / mitochondrial matrix / positive regulation of gene expression / perinuclear region of cytoplasm / magnesium ion binding / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / Golgi apparatus / 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 / 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
Chem-87R / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.16 Å
AuthorsOki, H. / Kondo, M. / Snell, G. / Lane, W.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of an Orally Bioavailable, Brain-Penetrating, in Vivo Active Phosphodiesterase 2A Inhibitor Lead Series for the Treatment of Cognitive Disorders.
Authors: Mikami, S. / Sasaki, S. / Asano, Y. / Ujikawa, O. / Fukumoto, S. / Nakashima, K. / Oki, H. / Kamiguchi, N. / Imada, H. / Iwashita, H. / Taniguchi, T.
History
DepositionMay 8, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 16, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 6, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Mar 27, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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 / _struct_conn.ptnr2_symmetry

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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
E: cGMP-dependent 3',5'-cyclic phosphodiesterase
F: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)244,24926
Polymers241,3926
Non-polymers2,85720
Water14,322795
1
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
E: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,4259
Polymers80,4642
Non-polymers9607
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3410 Å2
ΔGint-119 kcal/mol
Surface area28900 Å2
MethodPISA
2
B: cGMP-dependent 3',5'-cyclic phosphodiesterase
C: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,4008
Polymers80,4642
Non-polymers9366
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3270 Å2
ΔGint-113 kcal/mol
Surface area29270 Å2
MethodPISA
3
D: cGMP-dependent 3',5'-cyclic phosphodiesterase
F: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,4259
Polymers80,4642
Non-polymers9607
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3310 Å2
ΔGint-118 kcal/mol
Surface area28870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.925, 89.768, 90.361
Angle α, β, γ (deg.)107.31, 113.85, 89.84
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: 40232.051 Da / Num. of mol.: 6 / Fragment: UNP RESIDUES 578-919
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE2A / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O00408, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Mg
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-87R / 6-methyl-N-[(1R)-1-[4-(trifluoromethyloxy)phenyl]propyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide


Mass: 378.348 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C18H17F3N4O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 795 / 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: 2.12 Å3/Da / Density % sol: 41.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 100 mM tris HCl, pH 7.50, 410 mM magnesium chloride hexahydrate, 29.3%w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.97645 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 8, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97645 Å / Relative weight: 1
ReflectionResolution: 2.16→84.82 Å / Num. obs: 100556 / % possible obs: 96.8 % / Redundancy: 1.8 % / Net I/σ(I): 8.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementResolution: 2.16→84.82 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.913 / SU B: 7.485 / SU ML: 0.186 / Cross valid method: THROUGHOUT / ESU R: 0.37 / ESU R Free: 0.245
RfactorNum. reflection% reflectionSelection details
Rfree0.25635 5035 5 %RANDOM
Rwork0.20179 ---
obs0.20452 95501 94.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 26.626 Å2
Baniso -1Baniso -2Baniso -3
1-1.37 Å2-1.09 Å2-0.6 Å2
2--1.83 Å2-1.26 Å2
3----1.07 Å2
Refinement stepCycle: 1 / Resolution: 2.16→84.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16421 0 176 795 17392
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.01916999
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.9421.95922953
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.29751999
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.61823.824850
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.686153030
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.32115102
X-RAY DIFFRACTIONr_chiral_restr0.0730.22444
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.02113092
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.7143.3028014
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.7565.55710004
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.8033.6918985
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined6.2519.91527696
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: 2.164→2.22 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.311 298 -
Rwork0.279 5228 -
obs--70.02 %

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