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- PDB-6kk0: Crystal structure of PDE4D catalytic domain complexed with compound 4e -

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Basic information

Entry
Database: PDB / ID: 6kk0
TitleCrystal structure of PDE4D catalytic domain complexed with compound 4e
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / PDE4 inhibitor
Function / homology
Function and homology information


signaling receptor regulator activity / negative regulation of heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel ...signaling receptor regulator activity / negative regulation of heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / adrenergic receptor signaling pathway / heterocyclic compound binding / regulation of cell communication by electrical coupling involved in cardiac conduction / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / DARPP-32 events / 3',5'-cyclic-AMP phosphodiesterase activity / positive regulation of heart rate / cAMP-mediated signaling / cAMP binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cellular response to cAMP / cellular response to epinephrine stimulus / calcium channel regulator activity / calcium channel complex / positive regulation of interleukin-2 production / regulation of heart rate / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / scaffold protein binding / G alpha (s) signalling events / nuclear membrane / transmembrane transporter binding / cilium / apical plasma membrane / centrosome / enzyme binding / nucleoplasm / metal ion binding / membrane / plasma membrane / cytosol
Similarity search - Function
Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / 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. ...Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / 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. / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-M36 / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.20008760676 Å
AuthorsHuang, Y.-Y. / He, X. / Luo, H.-B.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China21877134 China
National Natural Science Foundation of China81522041 China
National Natural Science Foundation of China21572279 China
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery and Optimization of alpha-Mangostin Derivatives as Novel PDE4 Inhibitors for the Treatment of Vascular Dementia.
Authors: Liang, J. / Huang, Y.Y. / Zhou, Q. / Gao, Y. / Li, Z. / Wu, D. / Yu, S. / Guo, L. / Chen, Z. / Huang, L. / Liang, S.H. / He, X. / Wu, R. / Luo, H.B.
History
DepositionJul 23, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 18, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2May 13, 2020Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.3Nov 22, 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
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)76,4108
Polymers75,1572
Non-polymers1,2536
Water5,386299
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2054
Polymers37,5791
Non-polymers6263
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area80 Å2
ΔGint-33 kcal/mol
Surface area14680 Å2
MethodPISA
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2054
Polymers37,5791
Non-polymers6263
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area80 Å2
ΔGint-33 kcal/mol
Surface area14960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.365, 77.984, 163.344
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 37578.594 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase
#2: Chemical ChemComp-M36 / 7-[8-methoxy-2,2-dimethyl-7-(3-methylbut-2-enyl)-5-oxidanyl-6-oxidanylidene-pyrano[3,2-b]xanthen-9-yl]oxyheptanoic acid


Mass: 536.613 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H36O8 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 299 / 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: 2.57 Å3/Da / Density % sol: 52.12 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.4
Details: .1 M HEPES (pH 7.4), 0.1 M MgCl2, 15-20% PEG 3350, 10% isopropanol, 25% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: OXFORD DIFFRACTION NOVA / Wavelength: 1.5418 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Jul 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→22.15 Å / Num. obs: 40067 / % possible obs: 97.08 % / Redundancy: 3.8 % / Biso Wilson estimate: 24.6036207088 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 20.03
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.0337 / Mean I/σ(I) obs: 3.137 / Num. unique obs: 4015 / % possible all: 93.8

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
CrysalisPro38.41data reduction
CrysalisPro38.41data scaling
PHASER1.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WQA

5wqa


Resolution: 2.20008760676→21.9287236346 Å / SU ML: 0.27899960966 / Cross valid method: FREE R-VALUE / σ(F): 1.36630594001 / Phase error: 23.9671757909
RfactorNum. reflection% reflection
Rfree0.247173095303 1897 4.84781886484 %
Rwork0.197869701281 --
obs0.200272535449 39131 97.969555856 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 28.5701106052 Å2
Refinement stepCycle: LAST / Resolution: 2.20008760676→21.9287236346 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5253 0 82 299 5634
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007906510655845444
X-RAY DIFFRACTIONf_angle_d0.8605967904627404
X-RAY DIFFRACTIONf_chiral_restr0.0445348687447842
X-RAY DIFFRACTIONf_plane_restr0.00587953175291005
X-RAY DIFFRACTIONf_dihedral_angle_d15.11906760213304
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2001-2.25510.3352922473611180.2634819075972612X-RAY DIFFRACTION97.3956475205
2.2551-2.3160.2895260194751260.245737664022642X-RAY DIFFRACTION98.0169971671
2.316-2.3840.3194482892841280.2311471273492604X-RAY DIFFRACTION98.167445203
2.384-2.46090.2691518094821420.2307455002392631X-RAY DIFFRACTION98.0898478953
2.4609-2.54870.3109193058221280.2256178214792638X-RAY DIFFRACTION98.3291859225
2.5487-2.65060.2973596296961280.2227324017142662X-RAY DIFFRACTION98.3779971791
2.6506-2.7710.2634397489491520.2218516062912624X-RAY DIFFRACTION98.2307147912
2.771-2.91680.262070943561260.2089513031612650X-RAY DIFFRACTION98.2307147912
2.9168-3.09910.2312743901211300.206759166922653X-RAY DIFFRACTION98.2697740113
3.0991-3.33760.2759428351461420.1951932123632668X-RAY DIFFRACTION98.0802792321
3.3376-3.6720.2294051657861590.1914989427942644X-RAY DIFFRACTION98.3163802175
3.672-4.20010.2311474416551530.174003013772673X-RAY DIFFRACTION97.9549393414
4.2001-5.27950.2348359354591350.1596413396082672X-RAY DIFFRACTION96.3611397185
5.2795-21.920.1549060014541300.1751634875072861X-RAY DIFFRACTION97.8410206084

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