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- PDB-5uwf: Crystal structure of human PDE10A in complex with inhibitor 16d -

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Basic information

Entry
Database: PDB / ID: 5uwf
TitleCrystal structure of human PDE10A in complex with inhibitor 16d
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHydrolase/Hydrolase Inhibitor / phosphodiesterase / 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-8Q7 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsXu, R. / Cedervall, E.P. / Sridhar, V. / Barker, R. / Aertgeerts, K.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.
Authors: Dyck, B. / Branstetter, B. / Gharbaoui, T. / Hudson, A.R. / Breitenbucher, J.G. / Gomez, L. / Botrous, I. / Marrone, T. / Barido, R. / Allerston, C.K. / Cedervall, E.P. / Xu, R. / Sridhar, V. ...Authors: Dyck, B. / Branstetter, B. / Gharbaoui, T. / Hudson, A.R. / Breitenbucher, J.G. / Gomez, L. / Botrous, I. / Marrone, T. / Barido, R. / Allerston, C.K. / Cedervall, E.P. / Xu, R. / Sridhar, V. / Barker, R. / Aertgeerts, K. / Schmelzer, K. / Neul, D. / Lee, D. / Massari, M.E. / Andersen, C.B. / Sebring, K. / Zhou, X. / Petroski, R. / Limberis, J. / Augustin, M. / Chun, L.E. / Edwards, T.E. / Peters, M. / Tabatabaei, A.
History
DepositionFeb 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 26, 2017Provider: repository / Type: Initial release
Revision 1.1May 10, 2017Group: Database references
Revision 1.2Oct 4, 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
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
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)80,0878
Polymers78,9652
Non-polymers1,1226
Water7,891438
1
C: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0444
Polymers39,4821
Non-polymers5613
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
D: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0444
Polymers39,4821
Non-polymers5613
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.718, 81.239, 158.609
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: 39482.309 Da / Num. of mol.: 2 / Fragment: UNP residues 449-789
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): Rosetta(DE3)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-8Q7 / 9-[(1S)-2,2-difluorocyclopropane-1-carbonyl]-6-[(4-methoxyphenyl)methyl]-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one


Mass: 471.480 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C22H19F2N5O3S
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 438 / 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: 2.01 Å3/Da / Density % sol: 38.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.5 / Details: 15%PEG3350,0.2M calcium acetate,20mM BME

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 0.97946 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Feb 15, 2017
RadiationMonochromator: Double crystal, non fixed exit slit / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.87→37.4 Å / Num. obs: 54103 / % possible obs: 100 % / Redundancy: 7.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.039 / Net I/σ(I): 11.9
Reflection shellResolution: 1.87→1.91 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.782 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 3463 / CC1/2: 0.84 / Rpim(I) all: 0.309 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5C2H

5c2h


Resolution: 1.87→37.396 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.23
RfactorNum. reflection% reflectionSelection details
Rfree0.2476 2000 3.7 %Random selection
Rwork0.1886 ---
obs0.1908 54020 99.98 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.87→37.396 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5303 0 0 438 5741
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0065437
X-RAY DIFFRACTIONf_angle_d0.8397376
X-RAY DIFFRACTIONf_dihedral_angle_d18.8531984
X-RAY DIFFRACTIONf_chiral_restr0.045799
X-RAY DIFFRACTIONf_plane_restr0.006944
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.87-1.91680.35411410.27373647X-RAY DIFFRACTION100
1.9168-1.96860.34741410.24923664X-RAY DIFFRACTION100
1.9686-2.02650.29591400.23743660X-RAY DIFFRACTION100
2.0265-2.09190.2731410.21953658X-RAY DIFFRACTION100
2.0919-2.16670.27981410.21223687X-RAY DIFFRACTION100
2.1667-2.25340.25221430.20313688X-RAY DIFFRACTION100
2.2534-2.3560.24021400.20093654X-RAY DIFFRACTION100
2.356-2.48010.27411420.2033706X-RAY DIFFRACTION100
2.4801-2.63550.25451430.20253707X-RAY DIFFRACTION100
2.6355-2.83890.28871410.20123693X-RAY DIFFRACTION100
2.8389-3.12450.26491450.20133749X-RAY DIFFRACTION100
3.1245-3.57630.24411440.183748X-RAY DIFFRACTION100
3.5763-4.50450.21921460.15723797X-RAY DIFFRACTION100
4.5045-37.40340.18881520.15363962X-RAY DIFFRACTION100
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)
11.3042-0.21370.05641.9330.04641.4760.22630.23280.0279-1.1722-0.2972-0.39060.01580.15490.03640.48480.09110.1980.23440.05650.232661.7748116.536915.2781
20.791-0.2185-0.15342.9815-0.3431.28150.0505-0.1224-0.0252-0.0356-0.157-0.1294-0.02380.03970.10270.13990.00230.04070.16630.00260.126754.7663116.664232.2486
31.3067-0.1429-0.56921.1148-0.2452.6128-0.03090.1751-0.1452-0.5603-0.0478-0.37810.17990.02720.09170.44060.00870.20520.2264-0.00260.318868.694370.02560.6209
42.3522-0.1106-0.71691.0942-0.26363.6021-0.23610.1539-0.1062-0.48680.2141-0.09040.1742-0.12880.02970.35130.01830.13270.1698-0.00910.217865.507477.18579.231
57.74824.5659-1.32375.79990.55162.0069-0.55320.290.1321-0.7290.5062-0.3664-0.00880.13920.07240.3410.01630.13440.23670.00890.336579.143879.90247.4986
62.7382-0.35620.05821.98350.39581.3945-0.0426-0.1987-0.2054-0.1070.0337-0.26760.10360.20650.01950.32520.06420.09820.210.01310.291870.282568.509421.89
77.5065-5.1557-3.61113.97553.70425.2802-0.5754-0.3424-0.0590.59350.3096-0.71790.4090.93470.2360.29280.11390.03310.3730.04960.470782.103974.697216.8709
88.26315.1899-0.79568.7178-1.95323.9351-0.1132-0.52941.14490.30220.1004-0.5033-0.31070.27170.02620.27560.02250.03870.2863-0.12370.472473.88993.282222.8853
96.86970.8092.0971.59920.75691.5132-0.24730.0942-0.124-0.16460.1884-0.4398-0.06180.23410.06540.35220.01430.16820.20110.01390.27175.154388.000614.9215
100.34880.997-0.90593.0929-3.65575.3850.06560.0167-0.09670.19630.19610.3516-0.1206-0.3163-0.2710.26480.06980.1170.2595-0.00380.266750.994278.438919.6739
111.32211.526-0.41884.708-2.36651.30980.0731-0.33230.03510.442-0.06680.3707-0.0774-0.0474-0.02210.42140.05650.07340.2519-0.02550.251749.754685.628924.6235
126.60090.3104-1.35191.4225-0.2621.9836-0.07420.17120.3663-0.21010.0336-0.1324-0.1669-0.08110.04550.30740.03260.06620.12890.00060.177460.729795.480811.6647
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN C AND RESID 446:562 )C446 - 562
2X-RAY DIFFRACTION2( CHAIN C AND RESID 563:768 )C563 - 768
3X-RAY DIFFRACTION3( CHAIN D AND RESID 446:518 )D446 - 518
4X-RAY DIFFRACTION4( CHAIN D AND RESID 519:544 )D519 - 544
5X-RAY DIFFRACTION5( CHAIN D AND RESID 545:562 )D545 - 562
6X-RAY DIFFRACTION6( CHAIN D AND RESID 563:615 )D563 - 615
7X-RAY DIFFRACTION7( CHAIN D AND RESID 616:633 )D616 - 633
8X-RAY DIFFRACTION8( CHAIN D AND RESID 634:651 )D634 - 651
9X-RAY DIFFRACTION9( CHAIN D AND RESID 652:681 )D652 - 681
10X-RAY DIFFRACTION10( CHAIN D AND RESID 682:706 )D682 - 706
11X-RAY DIFFRACTION11( CHAIN D AND RESID 707:732 )D707 - 732
12X-RAY DIFFRACTION12( CHAIN D AND RESID 733:769 )D733 - 769

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