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- PDB-6c7f: Crystal structure of human phosphodiesterase 2A with 1-(2-chloro-... -

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Basic information

Entry
Database: PDB / ID: 6c7f
TitleCrystal structure of human phosphodiesterase 2A with 1-(2-chloro-5-isobutoxy-phenyl)-N,4-dimethyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide
ComponentscGMP-dependent 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE / phosphodiesterase
Function / homology
Function and homology information


regulation of cGMP-mediated signaling / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / cellular response to macrophage colony-stimulating factor stimulus / cellular response to cGMP / negative regulation of cAMP-mediated signaling / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / heart valve development / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability ...regulation of cGMP-mediated signaling / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / cellular response to macrophage colony-stimulating factor stimulus / cellular response to cGMP / negative regulation of cAMP-mediated signaling / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / heart valve development / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / regulation of mitochondrion organization / establishment of endothelial barrier / aorta development / cGMP-mediated signaling / ventricular septum development / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / TPR domain binding / cGMP catabolic process / phosphate ion binding / cGMP effects / monocyte differentiation / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / regulation of cAMP-mediated signaling / cAMP binding / cellular response to transforming growth factor beta stimulus / cellular response to cAMP / cAMP-mediated signaling / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / synaptic membrane / cellular response to mechanical stimulus / positive regulation of inflammatory response / cellular response to xenobiotic stimulus / presynaptic membrane / G alpha (s) signalling events / mitochondrial outer membrane / mitochondrial inner membrane / mitochondrial matrix / positive regulation of gene expression / perinuclear region of cytoplasm / Golgi apparatus / negative regulation of transcription by RNA polymerase II / magnesium ion binding / endoplasmic reticulum / protein homodimerization activity / zinc ion binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic 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 ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-EOS / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.82 Å
AuthorsXu, R. / Aertgeerts, K.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Mathematical and Structural Characterization of Strong Nonadditive Structure-Activity Relationship Caused by Protein Conformational Changes.
Authors: Gomez, L. / Xu, R. / Sinko, W. / Selfridge, B. / Vernier, W. / Ly, K. / Truong, R. / Metz, M. / Marrone, T. / Sebring, K. / Yan, Y. / Appleton, B. / Aertgeerts, K. / Massari, M.E. / Breitenbucher, J.G.
History
DepositionJan 22, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 15, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 29, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Sep 26, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Mar 13, 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: cGMP-dependent 3',5'-cyclic phosphodiesterase
B: cGMP-dependent 3',5'-cyclic phosphodiesterase
C: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,27012
Polymers119,7293
Non-polymers1,5419
Water10,233568
1
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,4234
Polymers39,9101
Non-polymers5143
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,4234
Polymers39,9101
Non-polymers5143
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,4234
Polymers39,9101
Non-polymers5143
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)167.248, 73.004, 91.953
Angle α, β, γ (deg.)90.000, 110.330, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-1238-

HOH

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Components

#1: Protein cGMP-dependent 3',5'-cyclic phosphodiesterase / Cyclic GMP-stimulated phosphodiesterase / cGSPDE


Mass: 39909.824 Da / Num. of mol.: 3 / Fragment: phosphodiesterase 2A (UNP residues 323-661)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE2A / Plasmid: pFastbac-HT / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: O00408, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical ChemComp-EOS / 1-[2-chloro-5-(2-methylpropoxy)phenyl]-N,4-dimethyl[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide


Mass: 423.895 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C22H22ClN5O2
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 568 / 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: 2.21 Å3/Da / Density % sol: 44.45 % / Mosaicity: 1.06 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.4
Details: 17-19% PEG3350, 0.2 M magnesium chloride, 0.1 M Tris, pH 8.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 19, 2016
RadiationMonochromator: Single crystal, cylindrically bent, Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 1.82→71.73 Å / Num. obs: 92617 / % possible obs: 99.5 % / Redundancy: 3.5 % / Biso Wilson estimate: 23.87 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.087 / Rpim(I) all: 0.054 / Rrim(I) all: 0.103 / Net I/σ(I): 8.7 / Num. measured all: 324430 / Scaling rejects: 69
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.82-1.873.41.18968760.6150.7491.41199.6
8.14-71.733.50.01910890.9990.0110.02298.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
DIALSdata reduction
Aimless0.5.23data scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.82→71.73 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 27.61
RfactorNum. reflection% reflection
Rfree0.2463 4549 4.92 %
Rwork0.1952 --
obs0.1977 92491 99.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 126.79 Å2 / Biso mean: 36.7351 Å2 / Biso min: 11.39 Å2
Refinement stepCycle: final / Resolution: 1.82→71.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8150 0 96 568 8814
Biso mean--27.51 37.68 -
Num. residues----994
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0078447
X-RAY DIFFRACTIONf_angle_d1.02311406
X-RAY DIFFRACTIONf_chiral_restr0.0411212
X-RAY DIFFRACTIONf_plane_restr0.0051478
X-RAY DIFFRACTIONf_dihedral_angle_d14.5173118
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.82-1.84070.34951530.33212934308799
1.8407-1.86230.31311530.32382937309099
1.8623-1.88510.38071710.30292854302599
1.8851-1.90890.35291270.30272968309599
1.9089-1.9340.35131430.28652912305599
1.934-1.96050.28331590.278629063065100
1.9605-1.98850.29361580.267929143072100
1.9885-2.01820.29281490.254429283077100
2.0182-2.04980.31281350.2422930306599
2.0498-2.08340.27681540.24362952310699
2.0834-2.11930.31421580.234928753033100
2.1193-2.15780.26081490.219129473096100
2.1578-2.19930.30921520.211829363088100
2.1993-2.24420.25331480.21082914306299
2.2442-2.2930.23111400.20442955309599
2.293-2.34640.24991530.20182913306699
2.3464-2.40510.24571300.18892955308599
2.4051-2.47010.26241380.1932945308399
2.4701-2.54280.25771580.19362928308699
2.5428-2.62490.26211450.18592905305099
2.6249-2.71870.21791470.18732927307499
2.7187-2.82750.28421790.19672896307599
2.8275-2.95620.26581450.20142941308699
2.9562-3.11210.26071670.19732895306299
3.1121-3.30710.22761450.17672943308899
3.3071-3.56240.24351760.18062896307299
3.5624-3.92090.20291590.15822949310899
3.9209-4.48820.18471500.15122945309599
4.4882-5.65430.20441450.15930153160100
5.6543-71.78620.22061630.17843027319099
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)
12.39720.62990.98851.54280.59813.94820.03090.2604-0.0685-0.06450.03790.04360.0307-0.0755-0.04510.16-0.00080.01130.14810.01710.143542.7507-7.136812.7533
23.2219-0.16341.31431.60470.08383.0481-0.11740.10870.34040.03160.0323-0.0558-0.53840.15940.03170.2813-0.03240.01340.10860.02040.190151.17046.561323.0085
38.1364-1.95877.49081.1621-1.54586.7816-0.2538-0.43940.14450.23280.1082-0.0073-0.2006-0.32470.13840.3374-0.00420.02390.2233-0.02370.201756.40772.163141.0815
41.87420.14690.11110.0565-0.33053.37740.15280.9576-0.3906-0.4367-0.311-0.49170.97021.10270.20640.47230.23060.0470.8272-0.06210.399477.0642-11.2506-25.8241
52.1849-0.81731.23221.4858-0.56352.74980.17880.7716-0.22730.0082-0.1357-0.25730.39370.89180.00910.23540.06520.0080.3786-0.02690.224872.9769-7.738-17.7915
64.0833-0.40030.65341.9575-0.05013.5804-0.11220.19230.07030.0778-0.0422-0.122-0.15040.09860.07650.1879-0.0205-0.00610.06450.04090.101462.96311.6754-12.0347
76.255-2.01123.0131.549-0.75113.5926-0.0426-0.1012-0.21060.35370.039-0.10590.08830.14410.00930.2425-0.02750.00780.14670.02380.193666.9143-6.2643-4.8182
87.5464-4.2024.9155.4028-2.93255.9234-0.8183-0.850.49350.6730.5668-0.314-0.361-0.24580.1640.26110.0374-0.02380.2298-0.00950.210570.8552.7935-3.6487
96.155.42341.00787.741.58681.0831-0.20630.21960.37630.912-0.3438-1.0587-0.94610.31840.48760.65-0.0403-0.29090.33670.13560.545964.825217.7191-15.8155
102.4918-0.5189-0.07013.24330.05452.7474-0.31240.40060.87140.4217-0.1304-0.6093-0.48080.70560.14110.3095-0.1366-0.15720.36140.15230.455772.567311.315-16.5249
118.47951.0925-0.51183.9657-0.89473.4357-0.02060.4306-0.1988-0.2615-0.06980.21050.3724-0.44450.0840.2209-0.0339-0.06390.3371-0.03830.174651.5539-0.6265-28.9106
122.99760.45270.82463.2179-0.29583.49510.02280.10210.2993-0.1267-0.34080.0935-0.35280.03580.17250.2189-0.0404-0.04180.30360.05880.233856.003510.6046-28.1855
136.61370.46814.63820.91960.43023.70080.36260.46020.023-0.3203-0.43690.0517-0.15010.6097-0.02620.3982-0.0422-0.02440.5940.07840.260555.38186.2686-40.9161
142.3220.63531.05961.68061.03992.48660.1289-0.6904-0.06330.221-0.11520.31880.1618-1.00080.00390.19230.00080.02010.57520.02090.226464.1748-41.141220.3855
151.0631-0.56880.13082.412-0.7233.72330.09440.4227-0.2712-0.14170.0499-0.33560.05330.488-0.05160.18380.06340.02210.41-0.06420.213577.7954-42.70738.1578
164.6551.67213.71164.14922.5115.7797-0.51620.7409-0.0476-0.8610.45340.3552-0.5243-0.17970.0690.2899-0.0755-0.04640.45810.02470.204568.4302-36.34453.6481
173.42820.70991.85492.3840.70083.3324-0.3309-0.12980.3363-0.01120.21790.0136-0.4916-0.09210.11020.23990.0334-0.02450.2884-0.06870.214277.4489-28.902219.2749
182.92340.09382.64752.2563-0.10383.725-0.2146-0.05110.3077-0.05610.0651-0.2143-0.66810.11430.2770.35820.0426-0.09240.341-0.09820.286485.731-27.164725.7352
195.1931-1.24473.84411.6244-0.78134.1375-0.302-0.30370.290.419-0.163-0.0469-0.6227-0.48370.11230.41310.0681-0.04270.5164-0.16170.274885.5582-28.929339.3276
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 579 through 768 )A579 - 768
2X-RAY DIFFRACTION2chain 'A' and (resid 769 through 878 )A769 - 878
3X-RAY DIFFRACTION3chain 'A' and (resid 879 through 917 )A879 - 917
4X-RAY DIFFRACTION4chain 'B' and (resid 582 through 611 )B582 - 611
5X-RAY DIFFRACTION5chain 'B' and (resid 612 through 674 )B612 - 674
6X-RAY DIFFRACTION6chain 'B' and (resid 675 through 724 )B675 - 724
7X-RAY DIFFRACTION7chain 'B' and (resid 725 through 750 )B725 - 750
8X-RAY DIFFRACTION8chain 'B' and (resid 751 through 768 )B751 - 768
9X-RAY DIFFRACTION9chain 'B' and (resid 769 through 785 )B769 - 785
10X-RAY DIFFRACTION10chain 'B' and (resid 786 through 815 )B786 - 815
11X-RAY DIFFRACTION11chain 'B' and (resid 816 through 840 )B816 - 840
12X-RAY DIFFRACTION12chain 'B' and (resid 841 through 878 )B841 - 878
13X-RAY DIFFRACTION13chain 'B' and (resid 879 through 917 )B879 - 917
14X-RAY DIFFRACTION14chain 'C' and (resid 590 through 695 )C590 - 695
15X-RAY DIFFRACTION15chain 'C' and (resid 696 through 750 )C696 - 750
16X-RAY DIFFRACTION16chain 'C' and (resid 751 through 768 )C751 - 768
17X-RAY DIFFRACTION17chain 'C' and (resid 769 through 840 )C769 - 840
18X-RAY DIFFRACTION18chain 'C' and (resid 841 through 878 )C841 - 878
19X-RAY DIFFRACTION19chain 'C' and (resid 879 through 916 )C879 - 916

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