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- PDB-6k9u: Discovery of Pyrazolo[1,5-a]pyrimidine Derivative as a Highly Sel... -

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Basic information

Entry
Database: PDB / ID: 6k9u
TitleDiscovery of Pyrazolo[1,5-a]pyrimidine Derivative as a Highly Selective PDE10A Inhibitor
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE / Enzyme / PDE / BBB / brain penetration / crystatl structure / inhibitor / schizophrenia
Function / homology
Function and homology information


cyclic-nucleotide phosphodiesterase activity / cGMP effects / G alpha (s) signalling events / extrinsic component of postsynaptic density membrane / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction ...cyclic-nucleotide phosphodiesterase activity / cGMP effects / G alpha (s) signalling events / extrinsic component of postsynaptic density membrane / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 3',5'-cyclic-AMP phosphodiesterase activity / : / cAMP binding / perikaryon / neuronal cell body / synapse / glutamatergic synapse / 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 / 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 ...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 / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / GAF-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-D4L / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsTakedomi, K. / Koizumi, Y.
CitationJournal: Bioorg.Med.Chem. / Year: 2019
Title: Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety.
Authors: Koizumi, Y. / Tanaka, Y. / Matsumura, T. / Kadoh, Y. / Miyoshi, H. / Hongu, M. / Takedomi, K. / Kotera, J. / Sasaki, T. / Taniguchi, H. / Watanabe, Y. / Takakuwa, M. / Kojima, K. / Baba, N. ...Authors: Koizumi, Y. / Tanaka, Y. / Matsumura, T. / Kadoh, Y. / Miyoshi, H. / Hongu, M. / Takedomi, K. / Kotera, J. / Sasaki, T. / Taniguchi, H. / Watanabe, Y. / Takakuwa, M. / Kojima, K. / Baba, N. / Nakamura, I. / Kawanishi, E.
History
DepositionJun 18, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 17, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 27, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_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: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5445
Polymers35,9141
Non-polymers6294
Water2,000111
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-33 kcal/mol
Surface area14260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.456, 120.456, 83.899
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

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Protein , 1 types, 1 molecules A

#1: Protein cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A


Mass: 35914.289 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Pde10a / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9QYJ6, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 115 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-D4L / 2-(3,7-dimethylquinoxalin-2-yl)-~{N}-(oxan-4-yl)-5-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidin-7-amine


Mass: 443.544 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H29N7O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 111 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Sequence detailsAuthors wrote that Phe452 is the N-terminal of PDE10 used in this experiment.

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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: 3.39 Å3/Da / Density % sol: 63.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5 / Details: Bicine, PEG2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jan 29, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.35→65.38 Å / Num. obs: 18913 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 6.3 % / Rsym value: 0.081 / Net I/σ(I): 17.65
Reflection shellResolution: 2.35→2.5 Å / Redundancy: 6.4 % / Num. unique obs: 3204 / Rsym value: 0.359 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.35→65.38 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.939 / SU B: 11.921 / SU ML: 0.146 / Cross valid method: THROUGHOUT / ESU R: 0.243 / ESU R Free: 0.195 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21475 905 4.8 %RANDOM
Rwork0.17501 ---
obs0.17688 17980 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 49.013 Å2
Baniso -1Baniso -2Baniso -3
1--1.25 Å2-0.63 Å20 Å2
2---1.25 Å20 Å2
3---1.88 Å2
Refinement stepCycle: LAST / Resolution: 2.35→65.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2462 0 40 111 2613
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222536
X-RAY DIFFRACTIONr_bond_other_d0.0010.022265
X-RAY DIFFRACTIONr_angle_refined_deg1.0951.9663445
X-RAY DIFFRACTIONr_angle_other_deg0.80335264
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9395306
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.87624.052116
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.42615430
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.8751513
X-RAY DIFFRACTIONr_chiral_restr0.0590.2374
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022794
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02518
X-RAY DIFFRACTIONr_nbd_refined0.2060.2598
X-RAY DIFFRACTIONr_nbd_other0.170.22205
X-RAY DIFFRACTIONr_nbtor_refined0.1770.21266
X-RAY DIFFRACTIONr_nbtor_other0.0860.21179
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1220.2107
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.1130.21
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1420.28
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2240.231
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1070.27
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.95721993
X-RAY DIFFRACTIONr_mcbond_other0.4332611
X-RAY DIFFRACTIONr_mcangle_it2.28532454
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.7841237
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.3846989
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.35→2.411 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.315 68 -
Rwork0.265 1348 -
obs--99.72 %
Refinement TLS params.Method: refined / Origin x: 17.727 Å / Origin y: 16.865 Å / Origin z: 27.437 Å
111213212223313233
T0.0462 Å2-0.0408 Å2-0.033 Å2-0.074 Å20.0417 Å2--0.0513 Å2
L2.256 °20.7313 °20.2995 °2-2.4407 °20.3467 °2--1.497 °2
S0.1356 Å °-0.3369 Å °-0.1069 Å °0.0995 Å °-0.1509 Å °-0.0318 Å °0.0738 Å °0.0477 Å °0.0153 Å °

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