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- PDB-3tgg: A novel series of potent and selective PDE5 inhibitor2 -

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Basic information

Entry
Database: PDB / ID: 3tgg
TitleA novel series of potent and selective PDE5 inhibitor2
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / phosphodiesterase / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of oocyte development / 3',5'-cyclic-GMP phosphodiesterase / regulation of nitric oxide mediated signal transduction / negative regulation of cardiac muscle contraction / oocyte development / RHOBTB1 GTPase cycle / relaxation of cardiac muscle / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects ...positive regulation of oocyte development / 3',5'-cyclic-GMP phosphodiesterase / regulation of nitric oxide mediated signal transduction / negative regulation of cardiac muscle contraction / oocyte development / RHOBTB1 GTPase cycle / relaxation of cardiac muscle / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / 3',5'-cyclic-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / Smooth Muscle Contraction / T cell proliferation / negative regulation of T cell proliferation / signal transduction / metal ion binding / 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-0H3 / cGMP-specific 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.91 Å
AuthorsHan, S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Investigation of the pyrazinones as PDE5 inhibitors: evaluation of regioisomeric projections into the solvent region.
Authors: Hughes, R.O. / Maddux, T. / Joseph Rogier, D. / Lu, S. / Walker, J.K. / Jon Jacobsen, E. / Rumsey, J.M. / Zheng, Y. / Macinnes, A. / Bond, B.R. / Han, S.
History
DepositionAug 17, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 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 / struct_ref_seq_dif / struct_site
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_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.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_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_ref_seq_dif.details / _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

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Assembly

Deposited unit
A: cGMP-specific 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1414
Polymers37,6101
Non-polymers5313
Water3,225179
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.493, 76.508, 76.811
Angle α, β, γ (deg.)90.00, 102.42, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein cGMP-specific 3',5'-cyclic phosphodiesterase / cGMP-binding cGMP-specific phosphodiesterase / CGB-PDE


Mass: 37610.211 Da / Num. of mol.: 1 / Fragment: Catalytic residues 534-858
Mutation: R658P, N662Q, S663F, Y664L, Q666T, R667N, Q674L, L675M, C677D, H678E, I680V, M681L, Q751E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE5A, PDE5 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: O76074, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-0H3 / 7-(6-methoxypyridin-3-yl)-4-{[2-(propan-2-yloxy)ethyl]amino}-1-(2-propoxyethyl)pyrido[4,3-d]pyrimidin-2(1H)-one


Mass: 441.523 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H31N5O4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 179 / 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: 2.08 Å3/Da / Density % sol: 40.83 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.2M MgSO4, 10-15%PEG3350, Tris, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 20, 2005
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.903→31 Å / Num. all: 23996 / Num. obs: 23482 / % possible obs: 98.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 23.94 Å2
Reflection shellResolution: 1.909→1.95 Å / % possible all: 95

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
BUSTER2.11.1refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.91→31 Å / Cor.coef. Fo:Fc: 0.9264 / Cor.coef. Fo:Fc free: 0.8862 / SU R Cruickshank DPI: 0.173 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2286 1206 5.14 %RANDOM
Rwork0.1861 ---
obs0.1883 23475 98.01 %-
Displacement parametersBiso mean: 25.89 Å2
Baniso -1Baniso -2Baniso -3
1-7.0633 Å20 Å2-1.0241 Å2
2--0.2181 Å20 Å2
3----7.2814 Å2
Refine analyzeLuzzati coordinate error obs: 0.202 Å
Refinement stepCycle: LAST / Resolution: 1.91→31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2619 0 34 179 2832
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012733HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.933719HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d983SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes80HARMONIC2
X-RAY DIFFRACTIONt_gen_planes409HARMONIC5
X-RAY DIFFRACTIONt_it2733HARMONIC20
X-RAY DIFFRACTIONt_nbd11SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.68
X-RAY DIFFRACTIONt_other_torsion17.14
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion355SEMIHARMONIC5
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_contact3185SEMIHARMONIC4
LS refinement shellResolution: 1.91→2 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2127 129 4.52 %
Rwork0.1845 2726 -
all0.1859 2855 -
obs--98.01 %
Refinement TLS params.Method: refined / Origin x: 9.1174 Å / Origin y: -0.0514 Å / Origin z: 19.2751 Å
111213212223313233
T-0.0269 Å2-0.0134 Å2-0.014 Å2--0.0309 Å20.0095 Å2---0.0522 Å2
L0.6725 °2-0.3433 °2-0.1516 °2-1.078 °20.3473 °2--0.5355 °2
S0.026 Å °0.0594 Å °0.0553 Å °-0.0235 Å °0.0077 Å °-0.0466 Å °-0.0141 Å °-0.0082 Å °-0.0338 Å °

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