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- PDB-5tzc: Crystal Structure of human PDE2a in complex with (5S)-1-[(3-bromo... -

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Basic information

Entry
Database: PDB / ID: 5tzc
TitleCrystal Structure of human PDE2a in complex with (5S)-1-[(3-bromo-4-fluorophenyl)carbonyl]-3,3-difluoro-5-{5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl}piperidine
ComponentscGMP-dependent 3',5'-cyclic phosphodiesterase
KeywordsHydrolase/Hydrolase Inhibitor / phosphodiesterase / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


: / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / cellular response to macrophage colony-stimulating factor stimulus / cellular response to cGMP / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / heart valve development / positive regulation of vascular permeability / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / establishment of endothelial barrier ...: / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / cellular response to macrophage colony-stimulating factor stimulus / cellular response to cGMP / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / heart valve development / positive regulation of vascular permeability / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / establishment of endothelial barrier / regulation of mitochondrion organization / : / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / aorta development / ventricular septum development / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cGMP effects / phosphate ion binding / TPR domain binding / cGMP binding / monocyte differentiation / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cellular response to transforming growth factor beta stimulus / : / cAMP binding / synaptic membrane / cellular response to cAMP / cellular response to mechanical stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cellular response to xenobiotic stimulus / positive regulation of inflammatory response / presynaptic membrane / G alpha (s) signalling events / mitochondrial outer membrane / mitochondrial inner membrane / mitochondrial matrix / positive regulation of gene expression / perinuclear region of cytoplasm / magnesium ion binding / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / Golgi apparatus / protein homodimerization activity / zinc ion binding / identical protein binding / nucleus / plasma membrane / cytoplasm / cytosol
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 / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / GAF-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-7OJ / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.36 Å
AuthorsXu, R. / Aertgeerts, K.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders.
Authors: Gomez, L. / Massari, M.E. / Vickers, T. / Freestone, G. / Vernier, W. / Ly, K. / Xu, R. / McCarrick, M. / Marrone, T. / Metz, M. / Yan, Y.G. / Yoder, Z.W. / Lemus, R. / Broadbent, N.J. / ...Authors: Gomez, L. / Massari, M.E. / Vickers, T. / Freestone, G. / Vernier, W. / Ly, K. / Xu, R. / McCarrick, M. / Marrone, T. / Metz, M. / Yan, Y.G. / Yoder, Z.W. / Lemus, R. / Broadbent, N.J. / Barido, R. / Warren, N. / Schmelzer, K. / Neul, D. / Lee, D. / Andersen, C.B. / Sebring, K. / Aertgeerts, K. / Zhou, X. / Tabatabaei, A. / Peters, M. / Breitenbucher, J.G.
History
DepositionNov 21, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2017Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Mar 6, 2024Group: 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_struct_conn_angle / struct_conn / struct_ncs_dom_lim
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 / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_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
D: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)162,84816
Polymers160,6724
Non-polymers2,17612
Water3,063170
1
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7124
Polymers40,1681
Non-polymers5443
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7124
Polymers40,1681
Non-polymers5443
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7124
Polymers40,1681
Non-polymers5443
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7124
Polymers40,1681
Non-polymers5443
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.850, 73.437, 91.322
Angle α, β, γ (deg.)109.600, 90.900, 91.240
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11SERSERGLUGLUAA576 - 9181 - 343
21SERSERGLUGLUBB576 - 9181 - 343
12METMETLEULEUAA578 - 9163 - 341
22METMETLEULEUCC578 - 9163 - 341
13TYRTYRLEULEUAA582 - 9167 - 341
23TYRTYRLEULEUDD582 - 9167 - 341
14METMETLEULEUBB578 - 9163 - 341
24METMETLEULEUCC578 - 9163 - 341
15TYRTYRLEULEUBB582 - 9167 - 341
25TYRTYRLEULEUDD582 - 9167 - 341
16TYRTYRLEULEUCC582 - 9167 - 341
26TYRTYRLEULEUDD582 - 9167 - 341

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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


Mass: 40168.051 Da / Num. of mol.: 4 / Fragment: catalytic domain, UNP residues 323-663
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE2A / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): baculovirus insect cell Hi5
References: UniProt: O00408, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical
ChemComp-7OJ / (3-bromo-4-fluorophenyl)[(5S)-3,3-difluoro-5-(5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]methanone


Mass: 454.244 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C18H15BrF3N5O
#3: Chemical
ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 170 / 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: 2.2 Å3/Da / Density % sol: 44.01 % / Mosaicity: 0.648 ° / Mosaicity esd: 0.01 °
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.4 / Details: 17-19% PEG3350, 0.2M MgCl2, 0.1M Tris, pH 8.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9761 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 31, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9761 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. obs: 55551 / % possible obs: 98.5 % / Redundancy: 2.1 % / Rmerge(I) obs: 0.105 / Rpim(I) all: 0.098 / Rrim(I) all: 0.144 / Χ2: 1.052 / Net I/av σ(I): 7.958 / Net I/σ(I): 6.1 / Num. measured all: 116391
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Diffraction-ID% possible all
2.35-2.432.10.3970.767197.6
2.43-2.532.10.3630.791198
2.53-2.652.10.3040.844198.1
2.65-2.792.10.2510.728198.2
2.79-2.962.10.2010.907198.5
2.96-3.192.10.1410.959198.6
3.19-3.512.10.10.973198.7
3.51-4.022.10.0710.985198.9
4.02-5.0620.0470.994199.1
5.06-502.10.0390.997199.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation8.48 Å46.77 Å
Translation8.48 Å46.77 Å

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHASER2.5.2phasing
REFMAC5.7.0029refinement
PDB_EXTRACT3.2data extraction
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.36→46.81 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.902 / SU B: 17.305 / SU ML: 0.196 / SU R Cruickshank DPI: 0.6271 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.627 / ESU R Free: 0.27
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2401 2828 5.1 %RANDOM
Rwork0.2005 ---
obs0.2025 52721 98.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 137.48 Å2 / Biso mean: 30.215 Å2 / Biso min: 2.94 Å2
Baniso -1Baniso -2Baniso -3
1--0.79 Å2-0.2 Å2-2.66 Å2
2--1.19 Å2-0.31 Å2
3----0.17 Å2
Refinement stepCycle: final / Resolution: 2.36→46.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11259 0 0 170 11429
Biso mean---19.11 -
Num. residues----1374
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.01911587
X-RAY DIFFRACTIONr_bond_other_d0.0070.0210850
X-RAY DIFFRACTIONr_angle_refined_deg1.4761.96115667
X-RAY DIFFRACTIONr_angle_other_deg1.264324985
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.451378
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.50123.833574
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.973152078
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1811569
X-RAY DIFFRACTIONr_chiral_restr0.080.21672
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213119
X-RAY DIFFRACTIONr_gen_planes_other0.0070.022830
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A208540.1
12B208540.1
21A210170.08
22C210170.08
31A205940.09
32D205940.09
41B206570.1
42C206570.1
51B204950.09
52D204950.09
61C208320.07
62D208320.07
LS refinement shellResolution: 2.356→2.417 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 184 -
Rwork0.271 3787 -
all-3971 -
obs--94.68 %
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)
10.288-0.1110.23530.23470.03690.3177-0.0119-0.0498-0.0006-0.00970.01740.0239-0.0146-0.0107-0.00550.02630.00490.02180.032-0.01540.03941.002-0.4030.844
20.49880.14260.17460.10270.05130.2750.01410.0657-0.01260.01220.0131-0.0259-0.0243-0.0136-0.02710.04030.0180.01410.02290.00090.034118.085-3.181-38.64
30.33040.01070.12410.1278-0.14280.50390.01010.0128-0.0647-0.03390.0057-0.0616-0.0152-0.0045-0.01580.02850.00980.01860.0159-0.0160.062245.268-37.508-37.547
40.4649-0.11070.15840.13670.15090.3835-0.0165-0.0883-0.06560.00540.03690.0244-0.0102-0.0107-0.02040.01260.00820.0250.02940.02250.052728.415-33.9033.142
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A576 - 918
2X-RAY DIFFRACTION1A1001 - 1003
3X-RAY DIFFRACTION1A1101 - 1147
4X-RAY DIFFRACTION2B576 - 918
5X-RAY DIFFRACTION2B1001 - 1003
6X-RAY DIFFRACTION2B1101 - 1148
7X-RAY DIFFRACTION3C578 - 917
8X-RAY DIFFRACTION3C1001 - 1003
9X-RAY DIFFRACTION3C1101 - 1138
10X-RAY DIFFRACTION4D582 - 917
11X-RAY DIFFRACTION4D1001 - 1003
12X-RAY DIFFRACTION4D1101 - 1137

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