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Structure paper

TitleA polycyclic scaffold identified by structure-based drug design effectively inhibits the human P2X7 receptor.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 8283, Year 2025
Publish dateSep 15, 2025
AuthorsAdam C Oken / Andreea L Turcu / Eva Tzortzini / Kyriakos Georgiou / Jessica Nagel / Franka G Westermann / Marta Barniol-Xicota / Jonas Seidler / Ga-Ram Kim / So-Deok Lee / Annette Nicke / Yong-Chul Kim / Christa E Müller / Antonios Kolocouris / Santiago Vázquez / Steven E Mansoor /
PubMed AbstractThe P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits ...The P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Understanding species-specific pharmacological effects of existing antagonists has been challenging, in part due to the dearth of molecular information on receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the full-length wild-type human P2X7 receptor in apo closed and ATP-bound open state conformations and draw comparisons with structures of other orthologs. We also report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, termed UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with subnanomolar potency and high selectivity, revealing its significant therapeutic potential.
External linksNat Commun / PubMed:40954149 / PubMed Central
MethodsEM (single particle)
Resolution2.48 - 2.95 Å
Structure data

47490

9e3m

EMDB-47490, PDB-9e3m:
Cryo-EM structure of the human P2X7 receptor in the apo closed state
Method: EM (single particle) / Resolution: 2.48 Å

47491

9e3n

EMDB-47491, PDB-9e3n:
Cryo-EM structure of the human P2X7 receptor in the ATP-bound open state
Method: EM (single particle) / Resolution: 2.95 Å

47492

9e3o

EMDB-47492, PDB-9e3o:
Cryo-EM structure of the human P2X7 receptor in the UB-ALT-P30-bound inhibited state
Method: EM (single particle) / Resolution: 2.76 Å

47493

9e3p

EMDB-47493, PDB-9e3p:
Cryo-EM structure of the human P2X7 receptor in the UB-MBX-46-bound inhibited state
Method: EM (single particle) / Resolution: 2.53 Å

47494

9e3q

EMDB-47494, PDB-9e3q:
Cryo-EM structure of the mouse P2X7 receptor in the apo closed state
Method: EM (single particle) / Resolution: 2.53 Å

Chemicals

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

ChemComp-ZN:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-PLM:
PALMITIC ACID

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

PDB-1bd8:
STRUCTURE OF CDK INHIBITOR P19INK4D

PDB-1bd9:
HUMAN PHOSPHATIDYLETHANOLAMINE BINDING PROTEIN

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Ion Channel / Ligand-Gated Ion Channel / P2X Receptor / P2XR / Allosteric Antagonist / Agonist

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