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- PDB-6nji: Crystal Structure of the PDE4D Catalytic Domain and UCR2 Regulato... -

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Basic information

Entry
Database: PDB / ID: 6nji
TitleCrystal Structure of the PDE4D Catalytic Domain and UCR2 Regulatory Helix with T-49
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE4D / CAMP-SPECIFIC 3'5'-CYCLIC PHOSPHODIESTERASE 4D / UCR2 / cAMP / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


G alpha (s) signalling events / DARPP-32 events / adenylate cyclase-activating adrenergic receptor signaling pathway involved in positive regulation of heart rate / positive regulation of interleukin-5 production / negative regulation of relaxation of cardiac muscle / adrenergic receptor signaling pathway / 3',5'-cyclic-AMP phosphodiesterase / voltage-gated calcium channel complex / establishment of endothelial barrier / regulation of cardiac muscle cell contraction ...G alpha (s) signalling events / DARPP-32 events / adenylate cyclase-activating adrenergic receptor signaling pathway involved in positive regulation of heart rate / positive regulation of interleukin-5 production / negative regulation of relaxation of cardiac muscle / adrenergic receptor signaling pathway / 3',5'-cyclic-AMP phosphodiesterase / voltage-gated calcium channel complex / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / beta-2 adrenergic receptor binding / 3',5'-cyclic-AMP phosphodiesterase activity / smooth muscle contraction / cAMP catabolic process / negative regulation of cAMP-mediated signaling / cAMP-mediated signaling / regulation of cell communication by electrical coupling involved in cardiac conduction / 3',5'-cyclic-nucleotide phosphodiesterase activity / positive regulation of interleukin-2 production / regulation of signaling receptor activity / cAMP binding / regulation of ryanodine-sensitive calcium-release channel activity / negative regulation of heart contraction / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / calcium channel complex / positive regulation of interferon-gamma production / negative regulation of peptidyl-serine phosphorylation / cellular response to epinephrine stimulus / regulation of heart rate / neutrophil chemotaxis / cellular response to cAMP / multicellular organism growth / scaffold protein binding / ATPase binding / drug binding / ion channel binding / apical plasma membrane / T cell receptor signaling pathway / nuclear membrane / aging / centrosome / cellular response to lipopolysaccharide / G protein-coupled receptor signaling pathway / ubiquitin protein ligase binding / enzyme binding / membrane / plasma membrane / metal ion binding / cytosol
Phosphodiesterase 4 upstream conserved regions (UCR) / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / HD/PDEase domain / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / Phosphodiesterase 4 upstream conserved regions (UCR) / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily ...Phosphodiesterase 4 upstream conserved regions (UCR) / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / HD/PDEase domain / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / Phosphodiesterase 4 upstream conserved regions (UCR) / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / Orthogonal Bundle / Mainly Alpha
cAMP-specific 3',5'-cyclic phosphodiesterase 4D
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsFox III, D. / Fairman, J.W. / Gurney, M.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and StrokeNS078034 United States
CitationJournal: J.Med.Chem. / Year: 2019
Title: Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders.
Authors: Gurney, M.E. / Nugent, R.A. / Mo, X. / Sindac, J.A. / Hagen, T.J. / Fox III, D. / O'Donnell, J.M. / Zhang, C. / Xu, Y. / Zhang, H.T. / Groppi, V.E. / Bailie, M. / White, R.E. / Romero, D.L. / Vellekoop, A.S. / Walker, J.R. / Surman, M.D. / Zhu, L. / Campbell, R.F.
Validation Report
SummaryFull reportAbout validation report
History
DepositionJan 3, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 8, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2019Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,0758
Polymers85,1862
Non-polymers8896
Water1,24369
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0384
Polymers42,5931
Non-polymers4453
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0384
Polymers42,5931
Non-polymers4453
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)124.040, 85.660, 83.450
Angle α, β, γ (deg.)90.00, 110.41, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein/peptide cAMP-specific 3',5'-cyclic phosphodiesterase 4D / DPDE3 / PDE43


Mass: 42593.051 Da / Num. of mol.: 2 / Mutation: S579A, S581A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Plasmid: PEMB44 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Zinc
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Magnesium
#4: Chemical ChemComp-KR4 / 2-(4-{[4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-yl]amino}phenyl)ethan-1-ol


Mass: 354.833 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19ClN4O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / Source method: isolated from a natural source / Formula: H2O / Water

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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: 2.44 Å3/Da / Density % sol: 49.66 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 7.14
Details: 5.0MG/ML VCID7620 + 0.5MM T-049 1MM DTT, 0.1MM ZNCL2, 0.1MM MGCL2 (BATCH 1214023) AGAINST OPTIMIZATION MATRIX BASED ON CONDITION MORPHEUS C8, 47.47%V/V OF 2X MORPHEUS-PPT4 (FINAL = 11.8% W/V PEG1,000 , 11.8% W/V PEG3,350 , 11.8% W/V MPD), 0.03M NPS (SODIUM NITRATE, DISODIUM HYDROGEN PHOSPHATE, AMMONIUM SULFATE), 0.1M HEPES PH 7.14, CRYO-PROTECTED - DIRECT (ZQV4-6); TRAY ID 236552B5, VAPOR DIFFUSION, SITTING DROP, TEMPERATURE 289K
PH range: 7.14

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 17, 2012
RadiationMonochromator: DIAMOND (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.45→50 Å / Num. obs: 29617 / % possible obs: 97.9 % / Observed criterion σ(I): -3 / Redundancy: 3.3 % / Biso Wilson estimate: 56.07 Å2 / Rmerge(I) obs: 0.046 / Net I/σ(I): 20.27
Reflection shellResolution: 2.45→2.51 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.504 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 2177 / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.45→42.87 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.936 / SU B: 7.955 / SU ML: 0.178 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.41 / ESU R Free: 0.252 / Details: HYDROGENS HAVE BEEN ADDED IN THE
RfactorNum. reflection% reflectionSelection details
Rfree0.23 1504 5.1 %RANDOM
Rwork0.184 ---
Obs0.187 29616 99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 50.86 Å2
Baniso -1Baniso -2Baniso -3
1-0.8 Å20 Å20.06 Å2
2--1.3 Å20 Å2
3----1.66 Å2
Refinement stepCycle: LAST / Resolution: 2.45→42.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5210 0 54 69 5333
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal targetNumber
r_bond_refined_d0.0140.0195373
r_bond_other_d0.0040.024914
r_angle_refined_deg1.5341.9437340
r_angle_other_deg0.987311192
r_dihedral_angle_1_deg5.215669
r_dihedral_angle_2_deg36.7324.859249
r_dihedral_angle_3_deg14.99515822
r_dihedral_angle_4_deg23.7781522
r_chiral_restr0.0790.2866
r_gen_planes_refined0.0080.026173
r_gen_planes_other0.0050.021261
r_nbd_refined
r_nbd_other
r_nbtor_refined
r_nbtor_other
r_xyhbond_nbd_refined
r_xyhbond_nbd_other
r_metal_ion_refined
r_metal_ion_other
r_symmetry_vdw_refined
r_symmetry_vdw_other
r_symmetry_hbond_refined
r_symmetry_hbond_other
r_symmetry_metal_ion_refined
r_symmetry_metal_ion_other
r_mcbond_it
r_mcbond_other
r_mcangle_it
r_mcangle_other
r_scbond_it
r_scbond_other
r_scangle_it
r_scangle_other
r_long_range_B_refined
r_long_range_B_other
r_rigid_bond_restr
r_sphericity_free
r_sphericity_bonded
LS refinement shellResolution: 2.45→2.51 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.337 99 -
Rwork0.264 2075 -
Obs--98.95 %

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