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- PDB-6l6e: Human PDE5 catalytic core in complex with avanafil -

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Basic information

Entry
Database: PDB / ID: 6l6e
TitleHuman PDE5 catalytic core in complex with avanafil
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / phosphodiesterase isoform 5 / avanafil / enzyme-drug complex / co-crystallization / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of oocyte development / 3',5'-cyclic-GMP phosphodiesterase / regulation of nitric oxide mediated signal transduction / negative regulation of cardiac muscle contraction / oocyte development / RHOBTB1 GTPase cycle / relaxation of cardiac muscle / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects ...positive regulation of oocyte development / 3',5'-cyclic-GMP phosphodiesterase / regulation of nitric oxide mediated signal transduction / negative regulation of cardiac muscle contraction / oocyte development / RHOBTB1 GTPase cycle / relaxation of cardiac muscle / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / 3',5'-cyclic-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / Smooth Muscle Contraction / T cell proliferation / negative regulation of T cell proliferation / signal transduction / metal ion binding / cytosol
Similarity search - Function
3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain ...3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain
Similarity search - Domain/homology
Chem-E6L / cGMP-specific 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsHsieh, C.M. / Chan, N.L.
Funding support Taiwan, 2items
OrganizationGrant numberCountry
Ministry of Science and Technology (Taiwan)106-2113-M-002-021-MY3 Taiwan
Ministry of Science and Technology (Taiwan)107-2923-B-002-001-MY4 Taiwan
CitationJournal: J.Med.Chem. / Year: 2020
Title: Structure of Human Phosphodiesterase 5A1 Complexed with Avanafil Reveals Molecular Basis of Isoform Selectivity and Guidelines for Targeting alpha-Helix Backbone Oxygen by Halogen Bonding.
Authors: Hsieh, C.M. / Chen, C.Y. / Chern, J.W. / Chan, N.L.
History
DepositionOct 28, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 2, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: cGMP-specific 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,6615
Polymers38,9911
Non-polymers6704
Water1,56787
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Human Phosphodiesterase 5 functions as a monomer.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area500 Å2
ΔGint-69 kcal/mol
Surface area14210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.837, 75.837, 160.610
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Space group name HallP4nw2abw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+3/4
#3: y+1/2,-x+1/2,z+1/4
#4: x+1/2,-y+1/2,-z+1/4
#5: -x+1/2,y+1/2,-z+3/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein cGMP-specific 3',5'-cyclic phosphodiesterase / human phosphodiesterase isoform 5 / cGMP-binding cGMP-specific phosphodiesterase / CGB-PDE


Mass: 38990.863 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE5A, PDE5 / Plasmid: pET21b / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): star pLys
References: UniProt: O76074, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 91 molecules

#2: Chemical ChemComp-E6L / 4-[(3-chloranyl-4-methoxy-phenyl)methylamino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimid ine-5-carboxamide / Avanafil / Avanafil


Mass: 483.951 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26ClN7O3 / Comment: inhibitor*YM
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 87 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.96 Å3/Da / Density % sol: 58.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.2M MgSO4, 0.1M Na cacodylate pH 6.8, 18 % PEG 3350

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Data collection

DiffractionMean temperature: 110 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL15A1 / Wavelength: 1 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: May 17, 2016
RadiationMonochromator: LN2-Cooled Fixed-Exit Double Crystal Si(111) Monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.92→30 Å / Num. obs: 36777 / % possible obs: 99.9 % / Redundancy: 6.3 % / Biso Wilson estimate: 26.83 Å2 / Rpim(I) all: 0.027 / Rrim(I) all: 0.069 / Net I/σ(I): 23.36
Reflection shellResolution: 1.92→1.96 Å / Redundancy: 6.5 % / Mean I/σ(I) obs: 3.864 / Num. unique obs: 2399 / CC1/2: 0.901 / Rpim(I) all: 0.204 / Rrim(I) all: 0.526 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
PHENIX1.17_3644phasing
PHENIX1.17_3644refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2H40

2h40


Resolution: 1.92→27.57 Å / SU ML: 0.182 / Cross valid method: FREE R-VALUE / Phase error: 20.505
RfactorNum. reflection% reflection
Rfree0.2074 1833 5 %
Rwork0.1966 --
obs-36626 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 31.08 Å2
Refinement stepCycle: LAST / Resolution: 1.92→27.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2553 0 41 87 2681
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00882703
X-RAY DIFFRACTIONf_angle_d0.7883676
X-RAY DIFFRACTIONf_chiral_restr0.0635417
X-RAY DIFFRACTIONf_plane_restr0.005471
X-RAY DIFFRACTIONf_dihedral_angle_d19.2841998
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.92-1.970.2931380.23382611X-RAY DIFFRACTION99.7
1.97-2.030.24511380.21232632X-RAY DIFFRACTION100
2.03-2.090.2391390.19162639X-RAY DIFFRACTION100
2.09-2.170.241400.1862651X-RAY DIFFRACTION100
2.17-2.260.19461370.17992627X-RAY DIFFRACTION100
2.26-2.360.21081400.18922660X-RAY DIFFRACTION100
2.36-2.480.22541390.2052644X-RAY DIFFRACTION100
2.48-2.640.21431410.21162664X-RAY DIFFRACTION100
2.64-2.840.2961410.21952683X-RAY DIFFRACTION100
2.84-3.130.24921420.22852685X-RAY DIFFRACTION100
3.13-3.580.1991430.20612721X-RAY DIFFRACTION99.93
3.58-4.50.16831440.17322744X-RAY DIFFRACTION99.97
4.51-27.570.16751540.18222909X-RAY DIFFRACTION99.64

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