9mkf: Difference between revisions

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~~'''Unreleased structure'''~~

~~The entry~~ 9mkf is ~~ON HOLD until Paper~~ Publication

==Rat TRPV2 bound to AV2-1 agonist==

== Structural highlights ==

<table><tr><td colspan='2'>[[9mkf]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9MKF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9MKF FirstGlance]. <br>

</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.83Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BMB:1-[(4~{S})-1-(furan-2-ylsulfonyl)-3,4-dihydro-2~{H}-quinolin-4-yl]cyclopropane-1-carboxylic+acid'>A1BMB</scene>, <scene name='pdbligand=PEX:1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>PEX</scene></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9mkf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9mkf OCA], [https://pdbe.org/9mkf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9mkf RCSB], [https://www.ebi.ac.uk/pdbsum/9mkf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9mkf ProSAT]</span></td></tr>

</table>

== Function ==

[https://www.uniprot.org/uniprot/TRPV2_RAT 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).<ref>PMID:10201375</ref> <ref>PMID:15249591</ref>

== 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.

~~Authors~~:

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<ref>PMID:41913383</ref>

~~Description~~:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased~~ Structures]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Large Structures]]

[[Category: Rattus norvegicus]]

[[Category: Moiseenkova-Bell VY]]

[[Category: Pumroy RA]]

[[Category: Rocereta JA]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9mkf is ON HOLD  until Paper Publication
+==Rat TRPV2 bound to AV2-1 agonist==
+<StructureSection load='9mkf' size='340' side='right'caption='[[9mkf]], [[Resolution|resolution]] 2.83&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9mkf]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9MKF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9MKF FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.83&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BMB:1-[(4~{S})-1-(furan-2-ylsulfonyl)-3,4-dihydro-2~{H}-quinolin-4-yl]cyclopropane-1-carboxylic+acid'>A1BMB</scene>, <scene name='pdbligand=PEX:1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>PEX</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9mkf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9mkf OCA], [https://pdbe.org/9mkf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9mkf RCSB], [https://www.ebi.ac.uk/pdbsum/9mkf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9mkf ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/TRPV2_RAT 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).<ref>PMID:10201375</ref> <ref>PMID:15249591</ref>
+<div style="background-color:#fffaf0;">
+== 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.
-Authors:
+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<ref>PMID:41913383</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9mkf" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Rattus norvegicus]]
+[[Category: Moiseenkova-Bell VY]]
+[[Category: Pumroy RA]]
+[[Category: Rocereta JA]]