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- PDB-5seu: CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c... -

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Basic information

Entry
Database: PDB / ID: 5seu
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c2(cn1nc(nc1cc2)CCc3nc(nn3C)N4CCCC4)C(F)(F)F, micromolar IC50=0.541196
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE inhibitor / PHOSPHODIESTERASE / PDE10 / HYDROLASE / SCHIZOPHRENIA / HYDROLASE-HYDROLASE inhibitor complex
Function / homology
Function and homology information


3',5'-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-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity ...3',5'-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-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / cAMP-mediated signaling / G alpha (s) signalling events / metal ion binding / cytosol
Similarity search - Function
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 ...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 / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain
Similarity search - Domain/homology
Chem-IHL / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09 Å
AuthorsJoseph, C. / Lerner, C. / Benz, J. / Schlatter, D. / Rudolph, M.G.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
F. Hoffmann-La Roche Switzerland
CitationJournal: J.Comput.Aided Mol.Des. / Year: 2022
Title: A high quality, industrial data set for binding affinity prediction: performance comparison in different early drug discovery scenarios.
Authors: Tosstorff, A. / Rudolph, M.G. / Cole, J.C. / Reutlinger, M. / Kramer, C. / Schaffhauser, H. / Nilly, A. / Flohr, A. / Kuhn, B.
History
DepositionJan 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 12, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 2, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 16, 2024Group: Structure summary
Category: pdbx_entry_details / pdbx_modification_feature / struct
Item: _pdbx_entry_details.has_protein_modification / _struct.title

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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
C: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
D: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)159,47316
Polymers157,6534
Non-polymers1,82012
Water6,449358
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8684
Polymers39,4131
Non-polymers4553
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8684
Polymers39,4131
Non-polymers4553
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8684
Polymers39,4131
Non-polymers4553
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8684
Polymers39,4131
Non-polymers4553
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.190, 135.190, 235.047
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3

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Components

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


Mass: 39413.203 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Plasmid: PET28a(+) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)pLysS
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-IHL / (4R)-2-{2-[1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl]ethyl}-6-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine


Mass: 365.356 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H18F3N7 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 358 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.62 Å3/Da / Density % sol: 53.09 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 5-20 mg/mL protein in 25mM HEPES/NaOH pH7.5, 150mM NaCl, 50mM BME mixed 1:1 with reservoir 0.1M HEPES/NaOH pH7.5, 30% PEG550MME, 50mM MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00001 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jun 4, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 2.09→43.49 Å / Num. obs: 94765 / % possible obs: 99.9 % / Redundancy: 5.158 % / Biso Wilson estimate: 50.443 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.07 / Rrim(I) all: 0.078 / Χ2: 0.844 / Net I/σ(I): 15.32 / Num. measured all: 488829 / Scaling rejects: 221
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.09-2.145.0521.6611.0835291699169860.4641.85699.9
2.14-2.24.7741.131.5632647684468390.5821.27299.9
2.2-2.274.9410.9761.8332846665966480.6741.09499.8
2.27-2.345.380.6522.7134805647464690.8220.72399.9
2.34-2.415.3360.4973.5533290624362390.8830.55299.9
2.41-2.55.3570.3994.4232472606860620.9230.44399.9
2.5-2.595.2910.2975.8530777581858170.950.33100
2.59-2.75.1860.2257.5929392566956680.9680.251100
2.7-2.824.8620.1898.8726238540053960.9760.21299.9
2.82-2.965.0910.14311.625942510550960.9870.1699.8
2.96-3.125.5260.10615.6327199492249220.9930.117100
3.12-3.35.4440.07820.6325231463646350.9960.086100
3.3-3.535.3040.05527.6923084435143520.9980.061100
3.53-3.825.1120.04333.9220802406940690.9980.048100
3.82-4.184.6610.03439.4517331372537180.9990.03999.8
4.18-4.675.120.0345.9217254337133700.9990.034100
4.67-5.45.3250.02849.315798296729670.9990.031100
5.4-6.615.2250.02847.713124251225120.9990.031100
6.61-9.354.7940.02253.789319194619440.9990.02499.9
9.35-43.495.670.01863.9259871065105610.0299.2

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.09→43.49 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.945 / SU B: 6.313 / SU ML: 0.154 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.198 / ESU R Free: 0.182 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: two conformations can be built into density, rotated about trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridine group. This places the trifluoromethyl-grou at the same spot but inverts the ...Details: two conformations can be built into density, rotated about trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridine group. This places the trifluoromethyl-grou at the same spot but inverts the triazolo[1,5-a]pyridine such that in one conformation, the hydrogen bond to Gln728 is longer than normal. not all protomers show density compatible with two conformations of the ligand.
RfactorNum. reflection% reflectionSelection details
Rfree0.238 4502 5 %RANDOM
Rwork0.1829 ---
obs0.1856 85571 94.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 121.12 Å2 / Biso mean: 45.701 Å2 / Biso min: 24.9 Å2
Baniso -1Baniso -2Baniso -3
1--0.3 Å2-0.15 Å20 Å2
2---0.3 Å20 Å2
3---0.99 Å2
Refinement stepCycle: final / Resolution: 2.09→43.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10152 0 164 358 10674
Biso mean--49.11 43.19 -
Num. residues----1251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01310596
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179668
X-RAY DIFFRACTIONr_angle_refined_deg1.6891.66514365
X-RAY DIFFRACTIONr_angle_other_deg1.41.58522481
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.14951251
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.75822.509550
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.246151850
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6581558
X-RAY DIFFRACTIONr_chiral_restr0.0850.21346
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211589
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022221
X-RAY DIFFRACTIONr_mcbond_it4.0774.6755004
X-RAY DIFFRACTIONr_mcbond_other4.0674.6735002
X-RAY DIFFRACTIONr_mcangle_it5.2516.9946249
LS refinement shellResolution: 2.09→2.144 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.388 299 -
Rwork0.359 5720 -
all-6019 -
obs--86.44 %

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