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TitleCannabinoid non-cannabidiol site modulation of TRPV2 structure and function.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 7483, Year 2022
Publish dateDec 5, 2022
AuthorsLiying Zhang / Charlotte Simonsen / Lucie Zimova / Kaituo Wang / Lavanya Moparthi / Rachelle Gaudet / Maria Ekoff / Gunnar Nilsson / Ute A Hellmich / Viktorie Vlachova / Pontus Gourdon / Peter M Zygmunt /
PubMed AbstractTRPV2 is a ligand-operated temperature sensor with poorly defined pharmacology. Here, we combine calcium imaging and patch-clamp electrophysiology with cryo-electron microscopy (cryo-EM) to explore ...TRPV2 is a ligand-operated temperature sensor with poorly defined pharmacology. Here, we combine calcium imaging and patch-clamp electrophysiology with cryo-electron microscopy (cryo-EM) to explore how TRPV2 activity is modulated by the phytocannabinoid Δ-tetrahydrocannabiorcol (C16) and by probenecid. C16 and probenecid act in concert to stimulate TRPV2 responses including histamine release from rat and human mast cells. Each ligand causes distinct conformational changes in TRPV2 as revealed by cryo-EM. Although the binding for probenecid remains elusive, C16 associates within the vanilloid pocket. As such, the C16 binding location is distinct from that of cannabidiol, partially overlapping with the binding site of the TRPV2 inhibitor piperlongumine. Taken together, we discover a new cannabinoid binding site in TRPV2 that is under the influence of allosteric control by probenecid. This molecular insight into ligand modulation enhances our understanding of TRPV2 in normal and pathophysiology.
External linksNat Commun / PubMed:36470868 / PubMed Central
MethodsEM (single particle)
Resolution2.94 - 3.49 Å
Structure data

14745

7zjd

EMDB-14745, PDB-7zjd:
Transient receptor potential cation channel subfamily V member 2,Enhanced green fluorescent protein
Method: EM (single particle) / Resolution: 2.94 Å

14746

7zje

EMDB-14746, PDB-7zje:
C16-2
Method: EM (single particle) / Resolution: 3.12 Å

14747

7zjg

EMDB-14747, PDB-7zjg:
Probenecid
Method: EM (single particle) / Resolution: 3.49 Å

14748

7zjh

EMDB-14748, PDB-7zjh:
TRPV2-C16+Pro-2
Method: EM (single particle) / Resolution: 3.39 Å

14749

7zji

EMDB-14749, PDB-7zji:
Transient receptor potential cation channel subfamily V member 2,Enhanced green fluorescent protein
Method: EM (single particle) / Resolution: 3.4 Å

Source
  • rattus norvegicus (Norway rat)
  • muromegalovirus g4
KeywordsMEMBRANE PROTEIN / temperature sensor

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