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- PDB-4npw: Crystal structure of human PDE1B bound to inhibitor 19A (7,8-dime... -

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Basic information

Entry
Database: PDB / ID: 4npw
TitleCrystal structure of human PDE1B bound to inhibitor 19A (7,8-dimethoxy-N-[(2S)-1-(3-methyl-1H-pyrazol-5-yl)propan-2-yl]quinazolin-4-amine)
ComponentsCalcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


calmodulin-activated dual specificity 3',5'-cyclic-GMP, 3',5'-cyclic-AMP phosphodiesterase activity / calmodulin-activated 3',5'-cyclic-GMP phosphodiesterase activity / cellular response to macrophage colony-stimulating factor stimulus / serotonin metabolic process / dopamine catabolic process / cellular response to granulocyte macrophage colony-stimulating factor stimulus / Cam-PDE 1 activation / 3',5'-cyclic-nucleotide phosphodiesterase / cGMP effects / monocyte differentiation ...calmodulin-activated dual specificity 3',5'-cyclic-GMP, 3',5'-cyclic-AMP phosphodiesterase activity / calmodulin-activated 3',5'-cyclic-GMP phosphodiesterase activity / cellular response to macrophage colony-stimulating factor stimulus / serotonin metabolic process / dopamine catabolic process / cellular response to granulocyte macrophage colony-stimulating factor stimulus / Cam-PDE 1 activation / 3',5'-cyclic-nucleotide phosphodiesterase / cGMP effects / monocyte differentiation / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling / response to amphetamine / locomotory behavior / visual learning / G alpha (s) signalling events / calmodulin binding / neuronal cell body / metal ion binding / cytosol
Similarity search - Function
3'5'-cyclic nucleotide phosphodiesterase N-terminal / 3'5'-cyclic nucleotide phosphodiesterase N-terminal / 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 N-terminal / 3'5'-cyclic nucleotide phosphodiesterase N-terminal / 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-0NY / Dual specificity calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsPandit, J. / Evdomikov, A. / Mansour, M. / Simons, S.
CitationJournal: MEDCHEMCOMM / Year: 2014
Title: Small-molecule phosphodiesterase probes: discovery of potent and selective CNS-penetrable quinazoline inhibitors of PDE1
Authors: Humphrey, J.M. / Yang, E.X. / Am Ende, C.W. / Arnold, E.P. / Head, J.L. / Jenkinsonb, S. / Lebel, L.A. / Liras, S. / Pandit, J. / Samas, B. / Vajdos, F. / Simons, S.P. / Evdokimova, A. / ...Authors: Humphrey, J.M. / Yang, E.X. / Am Ende, C.W. / Arnold, E.P. / Head, J.L. / Jenkinsonb, S. / Lebel, L.A. / Liras, S. / Pandit, J. / Samas, B. / Vajdos, F. / Simons, S.P. / Evdokimova, A. / Mansour, M. / Menniti, F.S.
History
DepositionNov 22, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 16, 2014Provider: 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.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: Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5524
Polymers42,1351
Non-polymers4173
Water4,486249
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)88.782, 88.782, 134.806
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B / Cam-PDE 1B / 63 kDa Cam-PDE


Mass: 42134.945 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 142-507
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE1B, PDE1B1, PDES1B / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: Q01064, 3',5'-cyclic-nucleotide 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-0NY / 7,8-dimethoxy-N-[(2S)-1-(3-methyl-1H-pyrazol-5-yl)propan-2-yl]quinazolin-4-amine


Mass: 327.381 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N5O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 249 / 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: 3.15 Å3/Da / Density % sol: 60.98 %
Crystal growpH: 8.5
Details: 0.1 M TRIS-HCL, 0.2 M MGCL2, 125 UM 5-(5-BROMO-2-PROPOXYPHENYL)-3-PROPYL-1H-PYRAZOLO[4,3-D]PYRIMIDIN-7(6H)-ONE, 15% PEG 8000, PH 8.5, VAPOR DIFFUSION, TEMPERATURE 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.97872
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 27, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 42307 / % possible obs: 97.8 % / Redundancy: 8.1 % / Rmerge(I) obs: 0.101 / Net I/σ(I): 8
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 8.3 % / Rmerge(I) obs: 0.774 / % possible all: 99.4

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→27.82 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.939 / SU R Cruickshank DPI: 0.11 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.209 2116 5.01 %RANDOM
Rwork0.19 ---
obs0.191 42246 97.9 %-
Displacement parametersBiso mean: 32.68 Å2
Baniso -1Baniso -2Baniso -3
1--2.7529 Å20 Å20 Å2
2---2.7529 Å20 Å2
3---5.5057 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: LAST / Resolution: 1.9→27.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2597 0 26 249 2872
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012679HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.953629HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d938SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes66HARMONIC2
X-RAY DIFFRACTIONt_gen_planes388HARMONIC5
X-RAY DIFFRACTIONt_it2679HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.73
X-RAY DIFFRACTIONt_other_torsion16.88
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion357SEMIHARMONIC5
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_contact3402SEMIHARMONIC4
LS refinement shellResolution: 1.9→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2331 174 5.61 %
Rwork0.2094 2930 -
all0.2107 3104 -
obs--97.89 %

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