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- PDB-8pc4: MEMBRANE TARGET COMPLEX 1 -

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Basic information

Entry
Database: PDB / ID: 8pc4
TitleMEMBRANE TARGET COMPLEX 1
ComponentsN-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D
KeywordsMEMBRANE PROTEIN / Membrane / Target / Dimer / Drug
Function / homology
Function and homology information


N-acetylphosphatidylethanolamine-hydrolysing phospholipase D / N-acylphosphatidylethanolamine-specific phospholipase D activity / Biosynthesis of A2E, implicated in retinal degradation / negative regulation of eating behavior / N-acylethanolamine metabolic process / N-acylphosphatidylethanolamine metabolic process / smooth endoplasmic reticulum membrane / host-mediated modulation of intestinal microbiota composition / bile acid binding / phospholipid catabolic process ...N-acetylphosphatidylethanolamine-hydrolysing phospholipase D / N-acylphosphatidylethanolamine-specific phospholipase D activity / Biosynthesis of A2E, implicated in retinal degradation / negative regulation of eating behavior / N-acylethanolamine metabolic process / N-acylphosphatidylethanolamine metabolic process / smooth endoplasmic reticulum membrane / host-mediated modulation of intestinal microbiota composition / bile acid binding / phospholipid catabolic process / photoreceptor outer segment membrane / temperature homeostasis / response to isolation stress / positive regulation of brown fat cell differentiation / hippocampal mossy fiber to CA3 synapse / positive regulation of inflammatory response / nuclear envelope / presynaptic membrane / early endosome membrane / postsynaptic membrane / early endosome / neuron projection / Golgi membrane / neuronal cell body / Golgi apparatus / extracellular exosome / zinc ion binding / nucleoplasm / identical protein binding / cytoplasm
Similarity search - Function
N-acyl-phosphatidylethanolamine-hydrolysing phospholipase D / Beta-lactamase superfamily domain / Metallo-beta-lactamase / Ribonuclease Z/Hydroxyacylglutathione hydrolase-like
Similarity search - Domain/homology
1,2-Distearoyl-sn-glycerophosphoethanolamine / Chem-HCZ / N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsGarau, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Chem Biol / Year: 2025
Title: NAPE-PLD is target of thiazide diuretics.
Authors: Sara Chiarugi / Francesco Margheriti / Valentina De Lorenzi / Elisa Martino / Eleonora Germana Margheritis / Aldo Moscardini / Roberto Marotta / Antonio Chaves-Sanjuan / Cristina Del Seppia ...Authors: Sara Chiarugi / Francesco Margheriti / Valentina De Lorenzi / Elisa Martino / Eleonora Germana Margheritis / Aldo Moscardini / Roberto Marotta / Antonio Chaves-Sanjuan / Cristina Del Seppia / Giuseppe Federighi / Dominga Lapi / Tiziano Bandiera / Simona Rapposelli / Rossana Scuri / Martino Bolognesi / Gianpiero Garau /
Abstract: Thiazide and thiazide-like diuretics are among the most efficacious and used drugs for the treatment of hypertension, edema, and major cardiovascular outcomes. Despite more then than six decades of ...Thiazide and thiazide-like diuretics are among the most efficacious and used drugs for the treatment of hypertension, edema, and major cardiovascular outcomes. Despite more then than six decades of clinical use, the molecular target and mechanism of action by which these drugs cure hypertension after long-term use have remained mysterious. Here we report the discovery and validation of a previously unknown renal and extrarenal target of these antihypertensives, the membrane-associated phospholipase N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) of the endocannabinoid system. Structural and functional insights, together with preclinical studies in hypertensive rats, disclose the molecular and physiological basis by which thiazides cause acute diuresis and, at the same time, the distinctive chronic reduction of vascular resistance. Our results shed light on the mechanism of treatment of hypertension and will be useful for developing more efficacious medications for the management of vascular risk factors, as well as associated leukoencephalopathies and myelin disorders.
History
DepositionJun 9, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 5, 2025Group: Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_contact_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _pdbx_contact_author.email / _pdbx_entry_details.has_protein_modification
Revision 1.2Mar 12, 2025Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Apr 2, 2025Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D
B: N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,29019
Polymers91,3092
Non-polymers5,98117
Water68538
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7500 Å2
ΔGint-1 kcal/mol
Surface area27150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.389, 94.389, 442.325
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Space group name HallP652(x,y,z+1/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+5/6
#3: y,-x+y,z+1/6
#4: -y,x-y,z+2/3
#5: -x+y,-x,z+1/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+1/3
#8: -x,-y,z+1/2
#9: y,x,-z+2/3
#10: -y,-x,-z+1/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+5/6
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 57 through 71 or resid 73...
d_2ens_1(chain "B" and (resid 57 through 71 or resid 73...

NCS domain segments:

Ens-ID: ens_1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11SERSERTHRTHRAA57 - 7157 - 71
d_12LYSLYSPROPROAA73 - 7573 - 75
d_13ILEILEPROPROAA77 - 11577 - 115
d_14GLUGLUARGARGAA117 - 166117 - 166
d_15SERSERARGARGAA168 - 314168 - 314
d_16PHEPHELEULEUAA316 - 370316 - 370
d_17ALAALAASNASNAA372 - 388372 - 388
d_18ZNZNZNZNAC401
d_19ZNZNZNZNAD402
d_1103PE3PE3PE3PEAE403
d_111DXCDXCDXCDXCAF404
d_112DXCDXCDXCDXCAG405
d_113DXCDXCDXCDXCAH406
d_114DXCDXCDXCDXCAI407
d_115DXCDXCDXCDXCAJ408
d_21SERSERTHRTHRBB57 - 7157 - 71
d_22LYSLYSPROPROBB73 - 7573 - 75
d_23ILEILEPROPROBB77 - 11577 - 115
d_24GLUGLUARGARGBB117 - 166117 - 166
d_25SERSERARGARGBB168 - 314168 - 314
d_26PHEPHELEULEUBB316 - 370316 - 370
d_27ALAALAASNASNBB372 - 388372 - 388
d_28ZNZNZNZNBN603
d_29ZNZNZNZNBO604
d_2103PE3PE3PE3PEBP605
d_211DXCDXCDXCDXCAK409
d_212DXCDXCDXCDXCBL601
d_213DXCDXCDXCDXCBM602
d_214DXCDXCDXCDXCBQ606
d_215DXCDXCDXCDXCBR607

NCS oper: (Code: givenMatrix: (-0.457594414051, -0.877942766307, -0.140797199256), (-0.877979962222, 0.421106632606, 0.227640923191), (-0.140565067372, 0.227784334546, -0.963512199596)Vector: 44. ...NCS oper: (Code: given
Matrix: (-0.457594414051, -0.877942766307, -0.140797199256), (-0.877979962222, 0.421106632606, 0.227640923191), (-0.140565067372, 0.227784334546, -0.963512199596)
Vector: 44.4991379076, -30.2500232542, 362.034219848)

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D / N-acyl phosphatidylethanolamine phospholipase D / NAPE-PLD / NAPE-hydrolyzing phospholipase D


Mass: 45654.395 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NAPEPLD, C7orf18 / Production host: Escherichia phage EcSzw-2 (virus)
References: UniProt: Q6IQ20, N-acetylphosphatidylethanolamine-hydrolysing phospholipase D

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Non-polymers , 5 types, 55 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-3PE / 1,2-Distearoyl-sn-glycerophosphoethanolamine / 3-SN-PHOSPHATIDYLETHANOLAMINE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE


Mass: 748.065 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C41H82NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#4: Chemical
ChemComp-DXC / (3ALPHA,5BETA,12ALPHA)-3,12-DIHYDROXYCHOLAN-24-OIC ACID / DEOXYCHOLIC ACID


Mass: 392.572 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C24H40O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: detergent*YM
#5: Chemical ChemComp-HCZ / 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide


Mass: 297.739 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H8ClN3O4S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 3.11 Å3/Da / Density % sol: 60.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: Lithium Sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ELETTRA / Beamline: 11.2C / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 31, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.66→88.47 Å / Num. obs: 35073 / % possible obs: 100 % / Redundancy: 11.2 % / Biso Wilson estimate: 87.76 Å2 / Rmerge(I) obs: 0.142 / Net I/σ(I): 8.7
Reflection shellResolution: 2.86→3.02 Å / Rmerge(I) obs: 1.5 / Num. unique obs: 4539

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
MOSFLMdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.85→54.75 Å / SU ML: 0.5135 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 33.9187
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3011 1468 5.17 %
Rwork0.2651 26937 -
obs0.2669 28405 99.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 100.57 Å2
Refinement stepCycle: LAST / Resolution: 2.85→54.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5457 0 389 38 5884
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00816111
X-RAY DIFFRACTIONf_angle_d1.26128382
X-RAY DIFFRACTIONf_chiral_restr0.0678892
X-RAY DIFFRACTIONf_plane_restr0.00851019
X-RAY DIFFRACTIONf_dihedral_angle_d19.92462197
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 2.82148408728 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.85-2.950.51181540.46812577X-RAY DIFFRACTION98.56
2.95-3.070.43461460.42462580X-RAY DIFFRACTION99.02
3.07-3.210.38281310.35372640X-RAY DIFFRACTION99.5
3.21-3.380.3361370.33342652X-RAY DIFFRACTION99.54
3.38-3.590.351440.322628X-RAY DIFFRACTION99.53
3.59-3.870.30421360.27292672X-RAY DIFFRACTION99.57
3.87-4.260.25531510.24222697X-RAY DIFFRACTION99.93
4.26-4.870.23481410.21942727X-RAY DIFFRACTION99.86
4.87-6.130.33411600.23112765X-RAY DIFFRACTION99.97
6.14-54.750.27051680.24232999X-RAY DIFFRACTION99.78
Refinement TLS params.Method: refined / Origin x: -2.91861123212 Å / Origin y: 25.4107830206 Å / Origin z: 187.556216922 Å
111213212223313233
T0.921180366191 Å20.205877195543 Å20.028110544058 Å2-0.404430574264 Å2-0.052029358794 Å2--0.550016794814 Å2
L2.44905609561 °20.0461597490002 °21.04261779268 °2-0.909053585493 °20.189780647051 °2--1.93092398003 °2
S0.0182716997203 Å °0.0354099339788 Å °-0.0960513951019 Å °0.145555179622 Å °-0.0276515789406 Å °0.0214216050624 Å °-0.148105601556 Å °0.148081010159 Å °0.0367984021471 Å °
Refinement TLS groupSelection details: all

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