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Structure paper

TitleNAPE-PLD is target of thiazide diuretics.
Journal, issue, pagesCell Chem Biol, Vol. 32, Issue 3, Page 449-462.e5, Year 2025
Publish dateMar 20, 2025
AuthorsSara 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 /
PubMed AbstractThiazide 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.
External linksCell Chem Biol / PubMed:39999832
MethodsEM (single particle) / X-ray diffraction
Resolution2.8 - 15.0 Å
Structure data

EMDB-16931: NAPE-PLD dimer bound to a nanodisc
Method: EM (single particle) / Resolution: 13.0 Å

EMDB-16932: NAPE-PLD bound to a nanodisc
Method: EM (single particle) / Resolution: 15.0 Å

PDB-8p90:
TARGET COMPLEX 2
Method: X-RAY DIFFRACTION / Resolution: 2.8 Å

PDB-8p96:
TARGET COMPLEX 3
Method: X-RAY DIFFRACTION / Resolution: 2.86 Å

PDB-8pc4:
MEMBRANE TARGET COMPLEX 1
Method: X-RAY DIFFRACTION / Resolution: 2.85 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM

ChemComp-DXC:
(3ALPHA,5BETA,12ALPHA)-3,12-DIHYDROXYCHOLAN-24-OIC ACID / detergent*YM

ChemComp-PLP:
PYRIDOXAL-5'-PHOSPHATE

ChemComp-HOH:
WATER


ChemComp, No image

ChemComp-XBE:
Unknown entry

ChemComp-HCZ:
6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide

Source
  • Escherichia coli (E. coli)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Complex / Membrane / Enzyme / Transport / Vitamin B6 / Target / Dimer / Drug

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