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- PDB-4muw: Crystal Structure of PDE10A with Novel Keto-Benzimidazole Inhibitor -

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Basic information

Entry
Database: PDB / ID: 4muw
TitleCrystal Structure of PDE10A with Novel Keto-Benzimidazole Inhibitor
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE10A / phosphodiesterase 10A / inhibitors / Keto-Benzimidazoles / 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-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP 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-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
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-2F4 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.639 Å
AuthorsChmait, S. / Jordan, S.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A).
Authors: Hu, E. / Kunz, R.K. / Chen, N. / Rumfelt, S. / Siegmund, A. / Andrews, K. / Chmait, S. / Zhao, S. / Davis, C. / Chen, H. / Lester-Zeiner, D. / Ma, J. / Biorn, C. / Shi, J. / Porter, A. / ...Authors: Hu, E. / Kunz, R.K. / Chen, N. / Rumfelt, S. / Siegmund, A. / Andrews, K. / Chmait, S. / Zhao, S. / Davis, C. / Chen, H. / Lester-Zeiner, D. / Ma, J. / Biorn, C. / Shi, J. / Porter, A. / Treanor, J. / Allen, J.R.
History
DepositionSep 23, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 23, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2014Group: Database references
Revision 1.2Sep 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_asym_id / _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.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_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)83,83424
Polymers81,1512
Non-polymers2,68422
Water3,009167
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules

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

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


Theoretical massNumber of molelcules
Total (without water)126,03439
Polymers121,7263
Non-polymers4,30836
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation18_555z,-x+1/2,-y+1/21
crystal symmetry operation48_555-y+1/2,-z+1/2,x1
Buried area4050 Å2
ΔGint-24 kcal/mol
Surface area41670 Å2
MethodPISA
3
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules

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

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


Theoretical massNumber of molelcules
Total (without water)125,46933
Polymers121,7263
Non-polymers3,74330
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555-z,-x,y1
crystal symmetry operation10_555-y,z,-x1
Buried area3820 Å2
ΔGint-28 kcal/mol
Surface area39340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)252.659, 252.659, 252.659
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number196
Space group name H-MF23

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 40575.398 Da / Num. of mol.: 2 / Fragment: human PDE10a, residues 442-779
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Production host: Escherichia coli (E. coli)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 189 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-2F4 / 2-{4-[(6,7-difluoro-1H-benzimidazol-2-yl)amino]phenoxy}-N-methyl-3,4'-bipyridin-2'-amine


Mass: 444.436 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H18F2N6O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 167 / 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: 4.14 Å3/Da / Density % sol: 70.29 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 1.6M Ammonium Sulfate, 0.1M MES monohydrate, 10% v/v 1,4-Dioxane, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Jan 7, 2013 / Details: Osmic Varimax HF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.639→29.19 Å / Num. all: 39231 / Num. obs: 39179 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.639→2.69 Å / % possible all: 99.8

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.7.0032refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4DDL

4ddl


Resolution: 2.639→29.19 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.956 / SU B: 13.627 / SU ML: 0.142 / Cross valid method: THROUGHOUT / ESU R: 0.271 / ESU R Free: 0.201
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19574 1957 5 %RANDOM
Rwork0.17107 ---
all0.17237 37039 --
obs0.17237 37039 99.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 50.92 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.639→29.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5063 0 151 167 5381
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0195329
X-RAY DIFFRACTIONr_bond_other_d0.0010.024924
X-RAY DIFFRACTIONr_angle_refined_deg1.3361.9787228
X-RAY DIFFRACTIONr_angle_other_deg0.783.00111333
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3015622
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.89724.065246
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.88115922
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4961528
X-RAY DIFFRACTIONr_chiral_restr0.0910.2788
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215881
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021235
X-RAY DIFFRACTIONr_mcbond_it1.5393.8322494
X-RAY DIFFRACTIONr_mcbond_other1.5343.8312493
X-RAY DIFFRACTIONr_mcangle_it2.5035.743114
X-RAY DIFFRACTIONr_mcangle_other2.5035.7413115
X-RAY DIFFRACTIONr_scbond_it1.7694.1652835
X-RAY DIFFRACTIONr_scbond_other1.7234.1122761
X-RAY DIFFRACTIONr_scangle_other2.7186.0954011
X-RAY DIFFRACTIONr_long_range_B_refined5.83431.486326
X-RAY DIFFRACTIONr_long_range_B_other5.82230.6446136
LS refinement shellResolution: 2.639→2.707 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.313 135 -
Rwork0.286 2702 -
obs--99.79 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.45630.13870.07620.70620.16330.5333-0.0301-0.0077-0.0930.08060.00790.01120.0166-0.01760.02220.0648-0.01550.02470.02170.02670.08473.327990.369629.9365
20.97260.25110.34431.54-0.09540.6334-0.00160.1055-0.0755-0.0342-0.027-0.09490.02010.02060.02860.0418-0.02810.04270.09730.00640.0791-27.026858.613930.0872
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A442 - 759
2X-RAY DIFFRACTION1A1001 - 1010
3X-RAY DIFFRACTION2B454 - 759
4X-RAY DIFFRACTION2B801 - 809

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