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- PDB-4y86: Crystal structure of PDE9 in complex with racemic inhibitor C33 -

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Basic information

Entry
Database: PDB / ID: 4y86
TitleCrystal structure of PDE9 in complex with racemic inhibitor C33
ComponentsHigh affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Keywordshydrolase/hydrolase inhibitor / Phosphodiesterase 9A / inhibitor selectivity pocket / pharmacokinetics / enantiomeric differentiation / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


cGMP metabolic process / negative regulation of neural precursor cell proliferation / 3',5'-cyclic-GMP phosphodiesterase / cGMP catabolic process / positive regulation of cardiac muscle hypertrophy / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling ...cGMP metabolic process / negative regulation of neural precursor cell proliferation / 3',5'-cyclic-GMP phosphodiesterase / cGMP catabolic process / positive regulation of cardiac muscle hypertrophy / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling / positive regulation of long-term synaptic potentiation / sarcolemma / ruffle membrane / perikaryon / perinuclear region of cytoplasm / Golgi apparatus / signal transduction / endoplasmic reticulum / nucleoplasm / identical protein binding / metal ion binding / plasma membrane / 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. / Metal dependent phosphohydrolases with conserved 'HD' motif. ...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. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-49D / Chem-49E / High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.01 Å
AuthorsHuang, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM59791 United States
CitationJournal: Mol.Pharmacol. / Year: 2015
Title: Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.
Authors: Huang, M. / Shao, Y. / Hou, J. / Cui, W. / Liang, B. / Huang, Y. / Li, Z. / Wu, Y. / Zhu, X. / Liu, P. / Wan, Y. / Ke, H. / Luo, H.B.
History
DepositionFeb 16, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 16, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2015Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Feb 28, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
B: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,4738
Polymers123,5782
Non-polymers8956
Water4,594255
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules

B: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,4738
Polymers123,5782
Non-polymers8956
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_645-y+3/2,x-1/2,z+1/41
Buried area2220 Å2
ΔGint-107 kcal/mol
Surface area28510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.135, 104.135, 269.536
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A


Mass: 61789.078 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE9A / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: O76083, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 261 molecules

#2: Chemical ChemComp-49D / 6-{[(1S)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one


Mass: 357.837 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20ClN5O
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-49E / 6-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one


Mass: 357.837 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20ClN5O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 255 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.96 Å3/Da / Density % sol: 58.4 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: The PDE9A2 (8-10 mg/mL) in a buffer of 50 mM NaCl, 20 mM Tris-HCl, pH 7.5, 1 mM mercaptoethanol, and 1 mM EDTA was mixed with 2 mM C33 and crystallized against a well buffer of 1.8 - 2.0 M sodium formate.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→100 Å / Num. obs: 96827 / % possible obs: 97.2 % / Redundancy: 12.6 % / Net I/σ(I): 20.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
RefinementResolution: 2.01→97.14 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.939 / SU B: 4.445 / SU ML: 0.109 / Cross valid method: THROUGHOUT / ESU R: 0.131 / ESU R Free: 0.126 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24725 4732 4.9 %RANDOM
Rwork0.22276 ---
obs0.22395 92056 97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 40.214 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å20 Å20 Å2
2---0.04 Å20 Å2
3---0.08 Å2
Refinement stepCycle: LAST / Resolution: 2.01→97.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5357 0 54 255 5666
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0195560
X-RAY DIFFRACTIONr_bond_other_d0.0020.025216
X-RAY DIFFRACTIONr_angle_refined_deg1.0671.9687519
X-RAY DIFFRACTIONr_angle_other_deg0.7923.00312039
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9425646
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.37324.364275
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.5515996
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7771532
X-RAY DIFFRACTIONr_chiral_restr0.060.2809
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0216159
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021285
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_it1.6093.842590
X-RAY DIFFRACTIONr_mcbond_other1.6083.8372589
X-RAY DIFFRACTIONr_mcangle_it2.6195.7473234
X-RAY DIFFRACTIONr_mcangle_other2.6195.753235
X-RAY DIFFRACTIONr_scbond_it2.1644.1652970
X-RAY DIFFRACTIONr_scbond_other2.1644.1652971
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.4426.1344286
X-RAY DIFFRACTIONr_long_range_B_refined4.97931.1096779
X-RAY DIFFRACTIONr_long_range_B_other4.94431.0326683
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.007→2.059 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.47 335 -
Rwork0.457 5985 -
obs--87.37 %

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