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- PDB-8syc: Crystal structure of PDE3B in complex with GSK4394835A -

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Basic information

Entry
Database: PDB / ID: 8syc
TitleCrystal structure of PDE3B in complex with GSK4394835A
ComponentscGMP-inhibited 3',5'-cyclic phosphodiesterase 3B
KeywordsHYDROLASE / PDE3B / inhibitor
Function / homology
Function and homology information


cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / PDE3B signalling / calmodulin-activated 3',5'-cyclic-GMP phosphodiesterase activity / protein kinase B binding / negative regulation of cell adhesion mediated by integrin / guanyl-nucleotide exchange factor complex / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of cell adhesion / 3',5'-cyclic-nucleotide phosphodiesterase / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction ...cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / PDE3B signalling / calmodulin-activated 3',5'-cyclic-GMP phosphodiesterase activity / protein kinase B binding / negative regulation of cell adhesion mediated by integrin / guanyl-nucleotide exchange factor complex / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of cell adhesion / 3',5'-cyclic-nucleotide phosphodiesterase / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / regulation of angiogenesis / negative regulation of lipid catabolic process / negative regulation of angiogenesis / cAMP-mediated signaling / cellular response to insulin stimulus / G alpha (s) signalling events / angiogenesis / G protein-coupled receptor signaling pathway / Golgi apparatus / endoplasmic reticulum / membrane / metal ion binding / cytosol
Similarity search - Function
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. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain
Similarity search - Domain/homology
: / cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsConcha, N.O. / Nolte, R.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and SAR Study of Boronic Acid-Based Selective PDE3B Inhibitors from a Novel DNA-Encoded Library.
Authors: Rowley, A.M. / Yao, G. / Andrews, L. / Bedermann, A. / Biddulph, R. / Bingham, R. / Brady, J.J. / Buxton, R. / Cecconie, T. / Cooper, R. / Csakai, A. / Gao, E.N. / Grenier-Davies, M.C. / ...Authors: Rowley, A.M. / Yao, G. / Andrews, L. / Bedermann, A. / Biddulph, R. / Bingham, R. / Brady, J.J. / Buxton, R. / Cecconie, T. / Cooper, R. / Csakai, A. / Gao, E.N. / Grenier-Davies, M.C. / Lawler, M. / Lian, Y. / Macina, J. / Macphee, C. / Marcaurelle, L. / Martin, J. / McCormick, P. / Pindoria, R. / Rauch, M. / Rocque, W. / Shen, Y. / Shewchuk, L.M. / Squire, M. / Stebbeds, W. / Tear, W. / Wang, X. / Ward, P. / Xiao, S.
History
DepositionMay 25, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2024Group: 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: cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B
D: cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,2038
Polymers102,1092
Non-polymers1,0946
Water1,47782
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)78.586, 78.586, 166.339
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

#1: Protein cGMP-inhibited 3',5'-cyclic phosphodiesterase 3B / CGIPDE1 / CGIP1 / Cyclic GMP-inhibited phosphodiesterase B / CGI-PDE B


Mass: 51054.535 Da / Num. of mol.: 2 / Mutation: K691D, R783D, A831E, K880E, S981D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE3B / Production host: Escherichia coli (E. coli)
References: UniProt: Q13370, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-X5W / [3-[(4,7-dimethoxyquinolin-2-yl)carbonylamino]-5-[methyl-(phenylmethyl)carbamoyl]phenyl]-oxidanyl-oxidanylidene-boron


Mass: 498.315 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H25BN3O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.61 Å3/Da / Density % sol: 52.95 %
Description: 3-dimensional rod-like about 200 microns in length
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.2 M NaCl, 25%PEG3350,0.1 M bis-Tris pH6.5, cryo: 25% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.9655 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 10, 2021
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9655 Å / Relative weight: 1
ReflectionResolution: 2.68→71.16 Å / Num. obs: 18157 / % possible obs: 92.7 % / Redundancy: 4.8 % / CC1/2: 0.986 / Rmerge(I) obs: 0.34 / Net I/σ(I): 6.8
Reflection shellResolution: 2.68→3.022 Å / Redundancy: 8.6 % / Rmerge(I) obs: 1.648 / Num. unique obs: 907 / CC1/2: 0.511 / % possible all: 66.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
Aimlessdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→71.16 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.898 / SU B: 16.629 / SU ML: 0.306 / Cross valid method: THROUGHOUT / ESU R Free: 0.411 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22352 841 4.6 %RANDOM
Rwork0.17674 ---
obs0.17888 17311 65.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 49.957 Å2
Baniso -1Baniso -2Baniso -3
1-0.14 Å2-0 Å2-0 Å2
2--0.14 Å2-0 Å2
3----0.28 Å2
Refinement stepCycle: 1 / Resolution: 2.7→71.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5716 0 78 82 5876
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0135953
X-RAY DIFFRACTIONr_bond_other_d0.0010.0165398
X-RAY DIFFRACTIONr_angle_refined_deg1.3361.6498100
X-RAY DIFFRACTIONr_angle_other_deg1.2371.58312372
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4465704
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.75423.385325
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.97215930
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.0461525
X-RAY DIFFRACTIONr_chiral_restr0.0550.2748
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026807
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021437
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.3735.192834
X-RAY DIFFRACTIONr_mcbond_other3.3745.192833
X-RAY DIFFRACTIONr_mcangle_it5.4167.7753532
X-RAY DIFFRACTIONr_mcangle_other5.4157.7753533
X-RAY DIFFRACTIONr_scbond_it3.5325.5913119
X-RAY DIFFRACTIONr_scbond_other3.5315.5913120
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.7858.264569
X-RAY DIFFRACTIONr_long_range_B_refined8.61160.9387152
X-RAY DIFFRACTIONr_long_range_B_other8.6160.9377153
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 12018 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.06 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2D
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.015 1 -
Rwork0.35 75 -
obs--3.79 %

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