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- PDB-2chm: Crystal structure of N2 substituted pyrazolo pyrimidinones - a fl... -

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Basic information

Entry
Database: PDB / ID: 2chm
TitleCrystal structure of N2 substituted pyrazolo pyrimidinones - a flipped binding mode in PDE5
ComponentsCGMP-SPECIFIC 3', 5'-CYCLIC PHOSPHODIESTERASE, CAMP-SPECIFIC 3', 5'-CYCLIC PHOSPHODIESTERASE 4B
KeywordsHYDROLASE / PHOSPHODIESTERASE 5 / INHIBITOR / CHIMERA / ALLOSTERIC ENZYME / ALTERNATIVE SPLICING / CGMP / CGMP-BINDING / MAGNESIUM / METAL-BINDING / NUCLEOTIDE-BINDING / PHOSPHORYLATION / ZINC / CAMP
Function / homology
Function and homology information


negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of oocyte development / 3',5'-cyclic-GMP phosphodiesterase / regulation of nitric oxide mediated signal transduction / gamma-tubulin complex / negative regulation of relaxation of cardiac muscle / negative regulation of cardiac muscle contraction / 3',5'-cyclic-AMP phosphodiesterase / oocyte development / neutrophil homeostasis ...negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of oocyte development / 3',5'-cyclic-GMP phosphodiesterase / regulation of nitric oxide mediated signal transduction / gamma-tubulin complex / negative regulation of relaxation of cardiac muscle / negative regulation of cardiac muscle contraction / 3',5'-cyclic-AMP phosphodiesterase / oocyte development / neutrophil homeostasis / gamma-tubulin binding / regulation of cardiac muscle cell contraction / RHOBTB1 GTPase cycle / relaxation of cardiac muscle / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / leukocyte migration / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / excitatory synapse / DARPP-32 events / calcium channel regulator activity / cGMP binding / Smooth Muscle Contraction / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / T cell proliferation / negative regulation of T cell proliferation / cAMP binding / cellular response to epinephrine stimulus / positive regulation of interleukin-2 production / cAMP-mediated signaling / neutrophil chemotaxis / Z disc / positive regulation of type II interferon production / cellular response to xenobiotic stimulus / synaptic vesicle / T cell receptor signaling pathway / cellular response to lipopolysaccharide / transmembrane transporter binding / dendritic spine / postsynaptic density / centrosome / perinuclear region of cytoplasm / nucleus / metal ion binding / 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 / 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 ...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 / 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-3P4 / cGMP-specific 3',5'-cyclic phosphodiesterase / 3',5'-cyclic-AMP phosphodiesterase 4B
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsAllerton, C.M.N. / Barber, C.G. / Beaumont, K.C. / Brown, D.G. / Cole, S.M. / Ellis, D. / Lane, C.A.L. / Maw, G.N. / Mount, N.M. / Rawson, D.J. ...Allerton, C.M.N. / Barber, C.G. / Beaumont, K.C. / Brown, D.G. / Cole, S.M. / Ellis, D. / Lane, C.A.L. / Maw, G.N. / Mount, N.M. / Rawson, D.J. / Robinson, C.M. / Street, S.D.A. / Summerhill, N.W.
CitationJournal: J.Med.Chem. / Year: 2006
Title: A Novel Series of Potent and Selective Pde5 Inhibitors with Potential for High and Dose-Independent Oral Bioavailability
Authors: Allerton, C.M.N. / Barber, C.G. / Beaumont, K.C. / Brown, D.G. / Cole, S.M. / Ellis, D. / Lane, C.A.L. / Maw, G.N. / Mount, N.M. / Rawson, D.J. / Robinson, C.M. / Street, S.D.A. / Summerhill, N.W.
History
DepositionMar 15, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 8, 2006Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Mar 27, 2019Group: Data collection / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc ...entity_src_gen / pdbx_database_proc / pdbx_database_status / struct_biol
Item: _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_strain / _pdbx_database_status.recvd_author_approval
Revision 1.4May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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_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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CGMP-SPECIFIC 3', 5'-CYCLIC PHOSPHODIESTERASE, CAMP-SPECIFIC 3', 5'-CYCLIC PHOSPHODIESTERASE 4B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3335
Polymers37,6101
Non-polymers7224
Water9,278515
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)55.836, 76.656, 81.269
Angle α, β, γ (deg.)90.00, 102.58, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein CGMP-SPECIFIC 3', 5'-CYCLIC PHOSPHODIESTERASE, CAMP-SPECIFIC 3', 5'-CYCLIC PHOSPHODIESTERASE 4B / 3' / 5' CGMP-CYCLIC PHOPHODIESTERASE 5A CATALYTIC DOMAIN CHIMERA / CGB-PDE / CGMP-BINDING CGMP- ...3' / 5' CGMP-CYCLIC PHOPHODIESTERASE 5A CATALYTIC DOMAIN CHIMERA / CGB-PDE / CGMP-BINDING CGMP-SPECIFIC PHOSPHODIESTERASE / DPDE4 / PDE32


Mass: 37610.211 Da / Num. of mol.: 1
Fragment: CATALYTIC DOMAIN RESIDUES (RESIDUES 534-858 WITH SUBDOMAIN REPLACED WITH PDE4 SUBDOMAIN)
Source method: isolated from a genetically manipulated source
Details: 5-(5-ACETYL-2-BUTOXY-3-PYRIDINYL)-3-ETHYL-2 -(1-ETHYL-3-AZETIDINYL)-2,6-DIHYDRO-7H-PYRAZOLO (4,3-D) PYRIMIDIN-7-ONE
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: FASTBAC / Cell line (production host): High Five / Production host: TRICHOPLUSIA NI (cabbage looper)
References: UniProt: O76074, UniProt: Q07343, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 519 molecules

#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-3P4 / 5-[2-(BUT-3-EN-1-YLOXY)-5-(1-HYDROXYVINYL)PYRIDIN-3-YL]-3-ETHYL-2-(1-ETHYLAZETIDIN-3-YL)-1,2,6,7A-TETRAHYDRO-7H-PYRAZOLO[4,3-D]PYRIMIDIN-7-ONE / 5-(5-ACETYL-2-BUTOXY-3-PYRIDINYL)-3-ETHYL-2-(1-ETHYL-3-AZETIDINYL)-2,6-DIHYDRO-7H-PYRAZOLO (4,3-D) PYRIMIDIN-7-ONE


Mass: 437.515 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H29N6O3
#5: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 515 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsTHE CHIMERA HAS NEAR IDENTICAL ENZYME ACTIVITY AS WILD TYPE RECOMBINANT PDE5 CATALYTIC DOMAIN
Sequence detailsNOTE SUBDOMAIN CHIMERA DELETED PDE5A RESIDUES 657-681 AND INSERTED RESIDUES 657-681A FROM PDE4B

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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: 2.2 Å3/Da / Density % sol: 43.77 %
Crystal growpH: 6.5
Details: 30% PEG 2KMME, 0.1M MES PH6.5, 50MM AMMONIUM SULPHATE, pH 6.50

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418
DetectorType: RIGAKU IMAGE PLATE / Detector: IMAGE PLATE / Date: Jan 31, 2001 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.6→30 Å / Num. obs: 41016 / % possible obs: 92.9 % / Observed criterion σ(I): 2 / Redundancy: 3.42 % / Rmerge(I) obs: 0.05
Reflection shellResolution: 1.6→1.66 Å / Rmerge(I) obs: 0.11 / % possible all: 64.1

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Processing

Software
NameVersionClassification
CNX2002refinement
DENZOdata reduction
SCALEPACKdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: FROM PATENT

Resolution: 1.6→50 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2234 2052 4.7 %RANDOM
Rwork0.1947 ---
obs-40971 --
Solvent computationBsol: 43.796 Å2 / ksol: 0.352264 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.048 Å20 Å2-0.089 Å2
2--0.109 Å20 Å2
3----0.061 Å2
Refinement stepCycle: LAST / Resolution: 1.6→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2611 0 46 515 3172
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.634
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1PROTEIN_REP.PARAM
X-RAY DIFFRACTION2DNA-RNA_REP.PARAM
X-RAY DIFFRACTION3WATER_REP.PARAM
X-RAY DIFFRACTION4ION.PARAM
X-RAY DIFFRACTION5427387.PAR

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