9mkf

Rat TRPV2 bound to AV2-1 agonist

spinqualitylabelsall models 9mkf, resolution 2.83Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9mkf is a 4 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.83Å Ligands: A1BMB, PEX Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TRPV2_RAT Calcium-permeable, non-selective cation channel with an outward rectification. Seems to be regulated, at least in part, by growth factors, like IGF1, PDGF and morphogenetic neuropeptide/head activator. May transduce physical stimuli in mast cells. Activated by temperatures higher than 52 degrees Celsius; is not activated by vanilloids and acidic pH (By similarity). Publication Abstract from PubMed BACKGROUND AND PURPOSE: Transient receptor potential vanilloid 2 (TRPV2) is a non-selective cation channel implicated in immune cell functions. However, progress in understanding TRPV2 has been limited by a lack of potent and selective pharmacological tools, particularly those targeting the human variant. We aimed to identify and characterise a novel small-molecule activator of TRPV2. EXPERIMENTAL APPROACH: We screened a compound library using Ca(2+) imaging in HEK293 cells stably expressing mouse TRPV2. The lead compound AV2-1 was validated by concentration-response analyses, microfluorometric Ca(2+) assays, and electrophysiological recordings. Structural insights were obtained from cryoEM of TRPV2 in complex with AV2-1, and mutagenesis was performed to confirm binding site residues. The efficacy of AV2-1 was assessed in human peripheral blood-derived macrophages by Ca(2+) imaging, whole-cell electrophysiology and TIRF microscopy to detect Ca(2+) microdomains. KEY RESULTS: AV2-1 is a novel TRPV2 activator showing robust efficacy across mouse, rat and human orthologues. Structural analysis reveals that AV2-1 stabilises the channel in its active conformation by binding to an established intracellular pocket via TRPV2-specific residues His165 and Cys157, as confirmed by mutagenesis experiments. AV2-1 induces TRPV2-dependent global [Ca(2+)](i) signals, ionic currents and localised subplasmalemmal Ca(2+) microdomains in human peripheral blood-derived macrophages. CONCLUSION AND IMPLICATIONS: AV2-1 represents a novel pharmacological tool for probing TRPV2 function in immune cells, combining improved selectivity and potency with low toxicity. Its ability to activate human TRPV2 and elicit physiologically relevant Ca(2+) signals highlights its potential for advancing TRPV2 research and for therapeutic exploration in immune modulation and disease contexts. Defining AV2-1 as a novel pharmacological probe to target human and rodent TRPV2.,Leipe A, Rocereta JA, Pumroy RA, Leffler A, Schaefer M, Moiseenkova-Bell V, Hill K Br J Pharmacol. 2026 Mar 30. doi: 10.1111/bph.70413. PMID:41913383 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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