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- PDB-3hdz: Identification, Synthesis, and SAR of Amino Substituted Pyrido[3,... -

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Entry
Database: PDB / ID: 3hdz
TitleIdentification, Synthesis, and SAR of Amino Substituted Pyrido[3,2b]pryaziones as Potent and Selective PDE5 Inhibitors
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase,cAMP-specific 3',5'-cyclic phosphodiesterase 4A,cGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE / PDE5 / PDE-5 / inhibition / Alternative splicing / cAMP / Phosphoprotein / Polymorphism Allosteric enzyme / cGMP / cGMP-binding / Magnesium / Metal-binding / Nucleotide-binding / Zinc
Function / homology
Function and homology information


positive regulation of oocyte development / 3',5'-cyclic-GMP phosphodiesterase / regulation of protein kinase A signaling / regulation of nitric oxide mediated signal transduction / negative regulation of cardiac muscle contraction / 3',5'-cyclic-AMP phosphodiesterase / oocyte development / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / RHOBTB1 GTPase cycle / relaxation of cardiac muscle ...positive regulation of oocyte development / 3',5'-cyclic-GMP phosphodiesterase / regulation of protein kinase A signaling / regulation of nitric oxide mediated signal transduction / negative regulation of cardiac muscle contraction / 3',5'-cyclic-AMP phosphodiesterase / oocyte development / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / RHOBTB1 GTPase cycle / relaxation of cardiac muscle / extrinsic component of membrane / cGMP catabolic process / positive regulation of cardiac muscle hypertrophy / cGMP effects / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / DARPP-32 events / 3',5'-cyclic-GMP phosphodiesterase activity / Smooth Muscle Contraction / 3',5'-cyclic-AMP phosphodiesterase activity / negative regulation of T cell proliferation / cAMP binding / T cell proliferation / cAMP-mediated signaling / ruffle membrane / sensory perception of smell / cellular response to xenobiotic stimulus / G alpha (s) signalling events / G protein-coupled receptor signaling pathway / perinuclear region of cytoplasm / signal transduction / nucleoplasm / membrane / nucleus / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / 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. ...Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / 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 / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-PD6 / cGMP-specific 3',5'-cyclic phosphodiesterase / 3',5'-cyclic-AMP phosphodiesterase 4A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsCubbage, J.W. / Brown, D.G. / Jacobsen, E.J. / Walker, J.K. / Hughes, R.O.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors.
Authors: Owen, D.R. / Walker, J.K. / Jon Jacobsen, E. / Freskos, J.N. / Hughes, R.O. / Brown, D.L. / Bell, A.S. / Brown, D.G. / Phillips, C. / Mischke, B.V. / Molyneaux, J.M. / Fobian, Y.M. / ...Authors: Owen, D.R. / Walker, J.K. / Jon Jacobsen, E. / Freskos, J.N. / Hughes, R.O. / Brown, D.L. / Bell, A.S. / Brown, D.G. / Phillips, C. / Mischke, B.V. / Molyneaux, J.M. / Fobian, Y.M. / Heasley, S.E. / Moon, J.B. / Stallings, W.C. / Joseph Rogier, D. / Fox, D.N. / Palmer, M.J. / Ringer, T. / Rodriquez-Lens, M. / Cubbage, J.W. / Blevis-Bal, R.M. / Benson, A.G. / Acker, B.A. / Maddux, T.M. / Tollefson, M.B. / Bond, B.R. / Macinnes, A. / Yu, Y.
History
DepositionMay 7, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 7, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jun 21, 2017Group: Advisory / Data collection ...Advisory / Data collection / Database references / Source and taxonomy / Structure summary
Category: diffrn_radiation_wavelength / diffrn_source ...diffrn_radiation_wavelength / diffrn_source / entity / entity_name_com / entity_src_gen / pdbx_distant_solvent_atoms / struct / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _diffrn_radiation_wavelength.wavelength / _diffrn_source.pdbx_wavelength_list ..._diffrn_radiation_wavelength.wavelength / _diffrn_source.pdbx_wavelength_list / _entity.pdbx_description / _entity.pdbx_ec / _entity.pdbx_fragment / _entity_name_com.name / _struct.pdbx_descriptor / _struct_ref.db_code / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_db_isoform / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.pdbx_seq_align_end_ins_code / _struct_ref_seq.seq_align_end / _struct_ref_seq_dif.details
Revision 1.3Nov 1, 2017Group: Refinement description / Category: software
Revision 1.4Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.5Jul 26, 2023Group: Database references / Derived calculations
Category: citation / database_2 ...citation / database_2 / pdbx_struct_conn_angle / pdbx_struct_special_symmetry / struct_conn / struct_site
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: cGMP-specific 3',5'-cyclic phosphodiesterase,cAMP-specific 3',5'-cyclic phosphodiesterase 4A,cGMP-specific 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7354
Polymers37,3521
Non-polymers3833
Water6,936385
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)56.015, 76.502, 80.720
Angle α, β, γ (deg.)90.000, 102.900, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-861-

HOH

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Components

#1: Protein cGMP-specific 3',5'-cyclic phosphodiesterase,cAMP-specific 3',5'-cyclic phosphodiesterase 4A,cGMP-specific 3',5'-cyclic phosphodiesterase / cGMP-binding cGMP-specific phosphodiesterase / CGB-PDE / DPDE2 / PDE46 / cGMP-binding cGMP-specific ...cGMP-binding cGMP-specific phosphodiesterase / CGB-PDE / DPDE2 / PDE46 / cGMP-binding cGMP-specific phosphodiesterase / CGB-PDE


Mass: 37351.988 Da / Num. of mol.: 1
Fragment: PDE4A residues 456-480, PDE5A residues 536-657 682-858
Mutation: Residues 658-682 from PDE4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Description: Residues 658-682 from PDE4 / Gene: PDE5A, PDE5, PDE4A, DPDE2 / Plasmid: Fastbac / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): High5
References: UniProt: O76074, UniProt: P27815, 3',5'-cyclic-GMP phosphodiesterase, 3',5'-cyclic-AMP phosphodiesterase
#2: Chemical ChemComp-PD6 / 5-amino-1-butyl-7-phenyl-1,6-naphthyridin-4(1H)-one


Mass: 293.363 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H19N3O
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 385 / 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: 2.26 Å3/Da / Density % sol: 45.5 %
Crystal growMethod: vapor diffusion, sitting drop / Details: VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 103 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Details: mirrors
RadiationMonochromator: filter / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→25 Å / Num. all: 30784 / Num. obs: 30728 / % possible obs: 99.9 % / Redundancy: 3.98 % / Biso Wilson estimate: 14.4 Å2 / Rsym value: 0.052 / Χ2: 1.088 / Net I/σ(I): 26.796
Reflection shellResolution: 1.8→1.86 Å / Rmerge(I) obs: 0.087 / Mean I/σ(I) obs: 14.1 / Num. unique all: 3067 / Rsym value: 0.087 / Χ2: 0.822 / % possible all: 99.9

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.005data extraction
HKL-2000data collection
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→19.67 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.918 / WRfactor Rfree: 0.231 / WRfactor Rwork: 0.198 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.866 / SU B: 2.439 / SU ML: 0.078 / SU R Cruickshank DPI: 0.138 / SU Rfree: 0.124 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.138 / ESU R Free: 0.124 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21 1558 5.1 %RANDOM
Rwork0.179 ---
obs0.181 30707 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 98.73 Å2 / Biso mean: 17.821 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--0.46 Å20 Å20.79 Å2
2---0.19 Å20 Å2
3---1 Å2
Refinement stepCycle: LAST / Resolution: 1.8→19.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2617 0 24 385 3026
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222691
X-RAY DIFFRACTIONr_bond_other_d0.0010.021807
X-RAY DIFFRACTIONr_angle_refined_deg1.0091.9683639
X-RAY DIFFRACTIONr_angle_other_deg0.87134428
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9225324
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.04625.038131
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.07615499
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6621514
X-RAY DIFFRACTIONr_chiral_restr0.060.2411
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022952
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02519
X-RAY DIFFRACTIONr_nbd_refined0.2170.2728
X-RAY DIFFRACTIONr_nbd_other0.180.21923
X-RAY DIFFRACTIONr_nbtor_refined0.1780.21373
X-RAY DIFFRACTIONr_nbtor_other0.0850.21236
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1540.2286
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2140.222
X-RAY DIFFRACTIONr_symmetry_vdw_other0.260.235
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2540.229
X-RAY DIFFRACTIONr_mcbond_it0.5851.51704
X-RAY DIFFRACTIONr_mcbond_other0.1121.5645
X-RAY DIFFRACTIONr_mcangle_it0.86622615
X-RAY DIFFRACTIONr_scbond_it1.67531172
X-RAY DIFFRACTIONr_scangle_it2.5474.51023
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.239 103 -
Rwork0.187 2129 -
all-2232 -
obs--99.73 %

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