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- PDB-6iwi: Crystal structure of PDE5A in complex with a novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 6iwi
TitleCrystal structure of PDE5A in complex with a novel inhibitor
ComponentscGMP-specific 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE / PDE5A / Inhibitor / Complex structure
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-nucleotide phosphodiesterase activity / cGMP binding / Smooth Muscle Contraction / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / T cell proliferation / negative regulation of T cell proliferation / cAMP-mediated signaling / metal ion binding / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-B0C / cGMP-specific 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.155 Å
AuthorsZhang, X.L. / Xu, Y.C.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension.
Authors: Wang, Z. / Jiang, X. / Zhang, X. / Tian, G. / Yang, R. / Wu, J. / Zou, X. / Liu, Z. / Yang, X. / Wu, C. / Shi, J. / Li, J. / Suo, J. / Wang, Y. / Zhang, R. / Xu, Z. / Gong, X. / He, Y. / ...Authors: Wang, Z. / Jiang, X. / Zhang, X. / Tian, G. / Yang, R. / Wu, J. / Zou, X. / Liu, Z. / Yang, X. / Wu, C. / Shi, J. / Li, J. / Suo, J. / Wang, Y. / Zhang, R. / Xu, Z. / Gong, X. / He, Y. / Zhu, W. / Aisa, H.A. / Jiang, H. / Xu, Y. / Shen, J.
History
DepositionDec 5, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 11, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 23, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct_conn
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _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.ptnr2_auth_seq_id
Revision 1.2Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)40,6224
Polymers40,0911
Non-polymers5313
Water2,630146
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area100 Å2
ΔGint-35 kcal/mol
Surface area12750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.748, 74.748, 132.020
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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


Mass: 40091.090 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE5A, PDE5 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: O76074, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-B0C / N-[3-(4,5-diethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-propoxyphenyl]-2-(4-methylpiperazin-1-yl)acetamide


Mass: 441.566 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H35N5O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / 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: 2.66 Å3/Da / Density % sol: 53.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.1 M Tris-HCl, 0.2 M MgSO4, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 25, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 23729 / % possible obs: 100 % / Redundancy: 18.9 % / Biso Wilson estimate: 22.94 Å2 / Rmerge(I) obs: 0.13 / Rpim(I) all: 0.031 / Rrim(I) all: 0.134 / Χ2: 0.99 / Net I/σ(I): 6.9 / Num. measured all: 449327
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.15-2.1917.52.30312000.7540.562.3710.77699.9
2.19-2.231811390.7161.12999.9
2.23-2.2718.11.43511560.7280.3441.4762.207100
2.27-2.3218.82.16911700.9290.5062.2280.83100
2.32-2.3719.21.25811660.9260.2911.2910.792100
2.37-2.4218.51.04711670.9320.2471.0770.799100
2.42-2.4818.20.86411810.9610.2070.8890.793100
2.48-2.5518.80.63411530.9710.1480.6510.831100
2.55-2.6220.20.52911610.9830.1190.5420.822100
2.62-2.7120.10.42111780.9880.0950.4320.837100
2.71-2.81200.31911820.990.0720.3270.85100
2.81-2.9220.10.24311750.9920.0550.2490.861100
2.92-3.0519.50.19811750.9950.0460.2030.888100
3.05-3.2118.20.13811950.9960.0330.1420.941100
3.21-3.4119.20.1111930.9970.0260.1130.99100
3.41-3.6820.10.10211840.9970.0240.1051.304100
3.68-4.0519.90.08211960.9980.0190.0841.129100
4.05-4.6318.30.07212240.9980.0170.0741.097100
4.63-5.8318.80.06712260.9980.0160.0691.041100
5.83-5017.40.0613080.9980.0150.0620.95599.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation6.73 Å36.39 Å
Translation6.73 Å36.39 Å

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
PHASER2.6.1phasing
PHENIX1.12_2829refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.155→36.393 Å / SU ML: 0.26 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 23.34
RfactorNum. reflection% reflection
Rfree0.2265 1080 4.83 %
Rwork0.1854 --
obs0.1874 22358 94.23 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 88.54 Å2 / Biso mean: 29.395 Å2 / Biso min: 7.21 Å2
Refinement stepCycle: final / Resolution: 2.155→36.393 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2281 0 34 146 2461
Biso mean--27.36 36.75 -
Num. residues----290
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022358
X-RAY DIFFRACTIONf_angle_d0.4353195
X-RAY DIFFRACTIONf_chiral_restr0.034368
X-RAY DIFFRACTIONf_plane_restr0.003404
X-RAY DIFFRACTIONf_dihedral_angle_d15.7481429
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1548-2.25280.2988830.29991685176861
2.2528-2.37160.33911170.2442604272193
2.3716-2.52010.27311460.214927482894100
2.5201-2.71460.24881610.198627682929100
2.7146-2.98770.25761380.196128292967100
2.9877-3.41980.22681340.184728262960100
3.4198-4.30740.16651470.154428372984100
4.3074-36.39860.20471540.157229813135100
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)
10.00050.0015-0.00090.00680.0010.00460.0040.0060.0028-0.0220.0098-0.0059-0.013-0.0022-0.00030.2446-0.08720.06360.20470.06330.145828.1799-12.201-13.2947
20.00420.0049-0.00030.00490.00050.0007-0.00780.0165-0.0047-0.00710.0106-0.0254-0.01490.01010.01460.2188-0.1410.05440.1128-0.00570.096933.8933-14.2879-3.6404
30.0110.01250.0060.01490.00630.0028-0.00780.0317-0.0242-0.03750.03-0.02060.0008-0.01390.010.1808-0.0957-0.00560.11920.0050.090725.764-23.6284-11.5806
40.01640.02150.00960.02940.01020.00710.0307-0.0022-0.05820.00070.0207-0.03220.0163-0.00360.0930.1019-0.1649-0.01030.02030.00160.066628.1131-22.83283.0105
50.00180.0012-0.00030.0087-0.00330.0032-0.0020.00170.01-0.00560.00470.03750.0026-0.01190.00710.1571-0.1615-0.00410.18940.00630.128717.1452-28.7894-2.5769
60.00280.0005-0.00120.0047-0.00010.00040.00720.0016-0.01280.0091-0.00270.00220.00270.00140.00740.1681-0.1428-0.01770.0514-0.00610.09123.4801-36.2592-0.8598
70.0007-0.0014-0.00060.0014-0.00130.00120.04220.0063-0.02440.02390.0358-0.0180.02570.0173-00.2953-0.0525-0.11370.14460.02530.206336.3009-37.744315.2016
80.0088-0.0041-0.00960.01640.00540.01230.0248-0.0059-0.021-0.00070.008-0.00160.01280.01330.02170.1734-0.0779-0.07640.05050.00540.116334.2562-29.45129.0564
90.00160.0020.00250.00380.00420.006-0.0093-0.00280.00520.0126-0.0112-0.0052-0.0084-0.0012-0.01120.1578-0.0609-0.00830.057-0.00290.099929.3531-9.328815.931
100.00070.00030.0004-000.00160.0203-0.0093-0.00480.01980.0076-0.0068-0.0014-0.005400.2841-0.0667-0.0840.16880.0140.150231.7621-14.965824.0383
110.0048-0.002-0.00290.00070.00110.00150.0055-0.0016-0.00820.0060.002-0.01010.00390.0119-0.00080.1513-0.0086-0.11940.1116-0.00080.16341.273-28.455714.3579
120.0018-0.0025-0.00210.01260.00750.01370.0034-0.0029-0.01160.0311-0.0077-0.0228-0.02310.01480.01070.1897-0.0406-0.11370.1927-0.05660.19842.6953-15.736519.0649
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 536 through 554 )A536 - 554
2X-RAY DIFFRACTION2chain 'A' and (resid 555 through 581 )A555 - 581
3X-RAY DIFFRACTION3chain 'A' and (resid 582 through 604 )A582 - 604
4X-RAY DIFFRACTION4chain 'A' and (resid 605 through 679 )A605 - 679
5X-RAY DIFFRACTION5chain 'A' and (resid 680 through 705 )A680 - 705
6X-RAY DIFFRACTION6chain 'A' and (resid 706 through 723 )A706 - 723
7X-RAY DIFFRACTION7chain 'A' and (resid 724 through 748 )A724 - 748
8X-RAY DIFFRACTION8chain 'A' and (resid 749 through 771 )A749 - 771
9X-RAY DIFFRACTION9chain 'A' and (resid 772 through 788 )A772 - 788
10X-RAY DIFFRACTION10chain 'A' and (resid 789 through 823 )A789 - 823
11X-RAY DIFFRACTION11chain 'A' and (resid 824 through 836 )A824 - 836
12X-RAY DIFFRACTION12chain 'A' and (resid 837 through 860 )A837 - 860

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