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- PDB-4msc: Crystal structure of PDE10A2 with fragment ZT1595 (2-[(quinolin-7... -

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Basic information

Entry
Database: PDB / ID: 4msc
TitleCrystal structure of PDE10A2 with fragment ZT1595 (2-[(quinolin-7-yloxy)methyl]quinoline)
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / fragment screening / hydrolase / 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-[(quinolin-7-yloxy)methyl]quinoline / NICKEL (II) ION / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.47 Å
AuthorsSridhar, V. / Badger, J. / Logan, C. / Chie-Leon, B. / Nienaber, V.
CitationJournal: J Biomol Screen / Year: 2014
Title: Identification and optimization of PDE10A inhibitors using fragment-based screening by nanocalorimetry and X-ray crystallography.
Authors: Recht, M.I. / Sridhar, V. / Badger, J. / Bounaud, P.Y. / Logan, C. / Chie-Leon, B. / Nienaber, V. / Torres, F.E.
History
DepositionSep 18, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: 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 / 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_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 / _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: 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)79,4807
Polymers78,9582
Non-polymers5215
Water63135
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8834
Polymers39,4791
Non-polymers4043
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5973
Polymers39,4791
Non-polymers1172
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.380, 82.085, 155.926
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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


Mass: 39479.242 Da / Num. of mol.: 2 / Fragment: catalytic domain, UNP residues 439-779
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-2ZT / 2-[(quinolin-7-yloxy)methyl]quinoline


Mass: 286.327 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H14N2O
#3: Chemical
ChemComp-NI / NICKEL (II) ION / Nickel


Mass: 58.693 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ni
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 35 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE FOUR DIVALENT CATIONS ARE REPRESENTED BY NI BUT THIS IDENTIFICATION IS SPECULATIVE

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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: 2.08 Å3/Da / Density % sol: 40.93 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 18% PEG 4450, 0.2M calcium acetate, 50mM BME, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9794 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Aug 15, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9794 Å / Relative weight: 1
ReflectionResolution: 2.47→50 Å / Num. all: 24593 / Num. obs: 24593 / % possible obs: 99.9 % / Observed criterion σ(F): -4 / Observed criterion σ(I): -4 / Redundancy: 5.5 % / Rmerge(I) obs: 0.084 / Net I/σ(I): 17.4
Reflection shellResolution: 2.47→2.56 Å / Redundancy: 5.5 % / Rmerge(I) obs: 0.581 / Mean I/σ(I) obs: 3.4 / Num. unique all: 2424 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.5.0110refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2OUR

2our


Resolution: 2.47→48.8 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.913 / SU B: 12.148 / SU ML: 0.275 / Cross valid method: THROUGHOUT / ESU R: 0.918 / ESU R Free: 0.336 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.28131 1255 5.1 %RANDOM
Rwork0.23377 ---
obs0.23621 23287 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 61.855 Å2
Baniso -1Baniso -2Baniso -3
1-1.42 Å20 Å20 Å2
2---1.1 Å20 Å2
3----0.32 Å2
Refinement stepCycle: LAST / Resolution: 2.47→48.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5220 0 26 35 5281
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0225380
X-RAY DIFFRACTIONr_angle_refined_deg1.1331.9477308
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9935653
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.81423.992243
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.16315904
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2791526
X-RAY DIFFRACTIONr_chiral_restr0.0770.2812
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214058
X-RAY DIFFRACTIONr_mcbond_it0.6823269
X-RAY DIFFRACTIONr_mcangle_it1.2252.55284
X-RAY DIFFRACTIONr_scbond_it1.05732111
X-RAY DIFFRACTIONr_scangle_it1.6764.52024
LS refinement shellResolution: 2.47→2.528 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.372 103
Rwork0.343 1622

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