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- PDB-4yqh: 2-[2-(4-Phenyl-1H-imidazol-2-yl)ethyl]quinoxaline (Sunovion Compo... -

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Basic information

Entry
Database: PDB / ID: 4yqh
Title2-[2-(4-Phenyl-1H-imidazol-2-yl)ethyl]quinoxaline (Sunovion Compound 14) co-crystallized with PDE10A
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / inhibitor / PDE10A / co-crystal / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / cGMP effects / cAMP catabolic process / 3',5'-cyclic-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity ...cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / cGMP effects / cAMP catabolic process / 3',5'-cyclic-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / G alpha (s) signalling events / signal transduction / metal ion binding / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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 / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
2-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]quinoxaline / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.308 Å
AuthorsBurdi, D. / Herman, L. / Wang, T.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.
Authors: Burdi, D.F. / Campbell, J.E. / Wang, J. / Zhao, S. / Zhong, H. / Wei, J. / Campbell, U. / Shao, L. / Herman, L. / Koch, P. / Jones, P.G. / Hewitt, M.C.
History
DepositionMar 13, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2015Provider: repository / Type: Initial release
Revision 1.1May 6, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Source and taxonomy / Structure summary
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list / software / struct_keywords
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _software.classification / _struct_keywords.text
Revision 1.3Feb 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
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_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _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_asym_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
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,1028
Polymers74,3222
Non-polymers7806
Water86548
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1740 Å2
ΔGint-104 kcal/mol
Surface area27700 Å2
2
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5514
Polymers37,1611
Non-polymers3903
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5514
Polymers37,1611
Non-polymers3903
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.150, 81.495, 159.677
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A / PDE10A


Mass: 37160.816 Da / Num. of mol.: 2 / Fragment: UNP residues 449-769
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-4F7 / 2-[2-(4-phenyl-1H-imidazol-2-yl)ethyl]quinoxaline


Mass: 300.357 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H16N4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 48 / 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: 2.2 Å3/Da / Density % sol: 43.97 %
Crystal growTemperature: 291 K / Method: batch mode / Details: magnesium chloride, PEG3350

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 24, 2009
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.308→50 Å / Num. all: 29597 / Num. obs: 27707 / % possible obs: 94 % / Redundancy: 5.7 % / Net I/σ(I): 16.7

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Processing

Software
NameVersionClassification
REFMACrefinement
PDB_EXTRACT3.15data extraction
X-PLORrefinement
CNSrefinement
CNSphasing
RefinementResolution: 2.308→50 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.91 / SU B: 13.534 / SU ML: 0.306 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.573 / ESU R Free: 0.324 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.3007 1409 5.1 %RANDOM
Rwork0.2362 ---
obs0.2395 26298 93.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 85.62 Å2 / Biso mean: 55.643 Å2 / Biso min: 17.92 Å2
Baniso -1Baniso -2Baniso -3
1-6.69 Å20 Å20 Å2
2---4.41 Å20 Å2
3----2.29 Å2
Refinement stepCycle: final / Resolution: 2.308→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5175 0 50 48 5273
Biso mean--41.22 41.8 -
Num. residues----642
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0225355
X-RAY DIFFRACTIONr_angle_refined_deg1.2171.9567256
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2355640
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.5324.032248
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.57115928
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8911528
X-RAY DIFFRACTIONr_chiral_restr0.0780.2793
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.024044
X-RAY DIFFRACTIONr_nbd_refined0.2070.22605
X-RAY DIFFRACTIONr_nbtor_refined0.3010.23672
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1690.2159
X-RAY DIFFRACTIONr_metal_ion_refined0.0240.22
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2020.238
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3560.26
X-RAY DIFFRACTIONr_mcbond_it0.5391.53307
X-RAY DIFFRACTIONr_mcangle_it0.95925190
X-RAY DIFFRACTIONr_scbond_it1.08832376
X-RAY DIFFRACTIONr_scangle_it1.7284.52066
LS refinement shellResolution: 2.308→2.368 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.489 100 -
Rwork0.356 1816 -
all-1916 -
obs--89.57 %

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