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Structural insights into the orthosteric inhibition of P2X receptors by non-ATP analog antagonists.
Sheng, Danqi; Yue, Chen-Xi; Jin, Fei; Wang, Yao; Ichikawa, Muneyoshi; Yu, Ye; Guo, Chang-Run; Hattori, Motoyuki.
Afiliación
  • Sheng D; State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Bioactive Small Molecules, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, China.
  • Yue CX; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
  • Jin F; State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Bioactive Small Molecules, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, China.
  • Wang Y; State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Bioactive Small Molecules, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, China.
  • Ichikawa M; State Key Laboratory of Genetic Engineering, Department of Biochemistry and Biophysics, School of Life Sciences, Fudan University, Shanghai, China.
  • Yu Y; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
  • Guo CR; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
  • Hattori M; State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Bioactive Small Molecules, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, China.
Elife ; 122024 Apr 05.
Article en En | MEDLINE | ID: mdl-38578670
ABSTRACT
P2X receptors are extracellular ATP-gated ion channels that form homo- or heterotrimers and consist of seven subtypes. They are expressed in various tissues, including neuronal and nonneuronal cells, and play critical roles in physiological processes such as neurotransmission, inflammation, pain, and cancer. As a result, P2X receptors have attracted considerable interest as drug targets, and various competitive inhibitors have been developed. However, although several P2X receptor structures from different subtypes have been reported, the limited structural information of P2X receptors in complex with competitive antagonists hampers the understanding of orthosteric inhibition, hindering the further design and optimization of those antagonists for drug discovery. We determined the cryogenic electron microscopy (cryo-EM) structures of the mammalian P2X7 receptor in complex with two classical competitive antagonists of pyridoxal-5'-phosphate derivatives, pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) and pyridoxal phosphate-6-azophenyl-2',5'-disulfonic acid (PPADS), and performed structure-based mutational analysis by patch-clamp recording as well as molecular dynamics (MD) simulations. Our structures revealed the orthosteric site for PPADS/PPNDS, and structural comparison with the previously reported apo- and ATP-bound structures showed how PPADS/PPNDS binding inhibits the conformational changes associated with channel activation. In addition, structure-based mutational analysis identified key residues involved in the PPNDS sensitivity of P2X1 and P2X3, which are known to have higher affinity for PPADS/PPNDS than other P2X subtypes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenosina Trifosfato / Simulación de Dinámica Molecular Límite: Animals Idioma: En Revista: Elife Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenosina Trifosfato / Simulación de Dinámica Molecular Límite: Animals Idioma: En Revista: Elife Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido