6puu

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Current revision (09:27, 20 March 2024) (edit) (undo)
 
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<SX load='6puu' size='340' side='right' viewer='molstar' caption='[[6puu]], [[Resolution|resolution]] 3.70&Aring;' scene=''>
<SX load='6puu' size='340' side='right' viewer='molstar' caption='[[6puu]], [[Resolution|resolution]] 3.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6puu]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PUU OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6PUU FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6puu]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PUU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PUU FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CV1:(2R,3R,4S,5R,13R,14S,15R,16R)-24-amino-18-bromo-3,4,14,15-tetrahydroxy-7,9,11,25,26-pentaoxa-17,19,22-triaza-1-azonia-8,10-diphosphapentacyclo[18.3.1.1^2,5^.1^13,16^.0^17,21^]hexacosa-1(24),18,20,22-tetraene-8,10-diolate+8,10-dioxide'>CV1</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.7&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TRPM2, EREG1, KNP3, LTRPC2, TRPC7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CV1:(2R,3R,4S,5R,13R,14S,15R,16R)-24-amino-18-bromo-3,4,14,15-tetrahydroxy-7,9,11,25,26-pentaoxa-17,19,22-triaza-1-azonia-8+,10-diphosphapentacyclo[18.3.1.1^2,5^.1^13,16^.0^17,21^]hexacosa-1(24),18,20,22-tetraene-8,10-diolate+8,10-dioxide'>CV1</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6puu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6puu OCA], [http://pdbe.org/6puu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6puu RCSB], [http://www.ebi.ac.uk/pdbsum/6puu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6puu ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6puu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6puu OCA], [https://pdbe.org/6puu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6puu RCSB], [https://www.ebi.ac.uk/pdbsum/6puu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6puu ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/TRPM2_HUMAN TRPM2_HUMAN]] Isoform 1: Nonselective, voltage-independent cation channel that mediates Na(+) and Ca(2+) influx, leading to increased cytoplasmic Ca(2+) levels (PubMed:11960981, PubMed:12594222, PubMed:11385575, PubMed:11509734, PubMed:11804595, PubMed:15561722, PubMed:16601673, PubMed:19171771, PubMed:20660597, PubMed:27383051, PubMed:27068538). Extracellular calcium passes through the channel and increases channel activity by binding to the cytoplasmic domain and stabilizing the channel in an open conformation (PubMed:19171771). Also contributes to Ca(2+) release from intracellular stores in response to ADP-ribose (PubMed:19454650). Plays a role in numerous processes that involve signaling via intracellular Ca(2+) levels (Probable). Besides, mediates the release of lysosomal Zn(2+) stores in response to reactive oxygen species, leading to increased cytosolic Zn(2+) levels (PubMed:25562606, PubMed:27068538). Activated by moderate heat (35 to 40 degrees Celsius) (PubMed:16601673). Activated by intracellular ADP-ribose, beta-NAD (NAD(+)) and similar compounds, and by oxidative stress caused by reactive oxygen or nitrogen species (PubMed:11960981, PubMed:11385575, PubMed:11509734, PubMed:11804595, PubMed:15561722, PubMed:16601673, PubMed:19171771, PubMed:27383051, PubMed:27068538). The precise physiological activators are under debate; the true, physiological activators may be ADP-ribose and ADP-ribose-2'-phosphate (PubMed:20650899, PubMed:25918360). Activation by ADP-ribose and beta-NAD is strongly increased by moderate heat (35 to 40 degrees Celsius) (PubMed:16601673). Likewise, reactive oxygen species lower the threshold for activation by moderate heat (37 degrees Celsius) (PubMed:22493272). Plays a role in mediating behavorial and physiological responses to moderate heat and thereby contributes to body temperature homeostasis. Plays a role in insulin secretion, a process that requires increased cytoplasmic Ca(2+) levels (By similarity). Required for normal IFNG and cytokine secretion and normal innate immune immunity in response to bacterial infection. Required for normal phagocytosis and cytokine release by macrophages exposed to zymosan (in vitro). Plays a role in dendritic cell differentiation and maturation, and in dendritic cell chemotaxis via its role in regulating cytoplasmic Ca(2+) levels (By similarity). Plays a role in the regulation of the reorganization of the actin cytoskeleton and filopodia formation in response to reactive oxygen species via its role in increasing cytoplasmic Ca(2+) and Zn(2+) levels (PubMed:27068538). Confers susceptibility to cell death following oxidative stress (PubMed:12594222, PubMed:25562606).[UniProtKB:Q91YD4]<ref>PMID:11385575</ref> <ref>PMID:11509734</ref> <ref>PMID:11804595</ref> <ref>PMID:11960981</ref> <ref>PMID:12594222</ref> <ref>PMID:15561722</ref> <ref>PMID:16601673</ref> <ref>PMID:19171771</ref> <ref>PMID:19454650</ref> <ref>PMID:20650899</ref> <ref>PMID:20660597</ref> <ref>PMID:22493272</ref> <ref>PMID:25562606</ref> <ref>PMID:25918360</ref> <ref>PMID:27068538</ref> <ref>PMID:27383051</ref> Isoform 2: Lacks cation channel activity. Does not mediate cation transport in response to oxidative stress or ADP-ribose.<ref>PMID:11960981</ref> Isoform 3: Lacks cation channel activity and negatively regulates the channel activity of isoform 1. Negatively regulates susceptibility to cell death in reposponse to oxidative stress.<ref>PMID:12594222</ref>
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[https://www.uniprot.org/uniprot/TRPM2_HUMAN TRPM2_HUMAN] Isoform 1: Nonselective, voltage-independent cation channel that mediates Na(+) and Ca(2+) influx, leading to increased cytoplasmic Ca(2+) levels (PubMed:11960981, PubMed:12594222, PubMed:11385575, PubMed:11509734, PubMed:11804595, PubMed:15561722, PubMed:16601673, PubMed:19171771, PubMed:20660597, PubMed:27383051, PubMed:27068538). Extracellular calcium passes through the channel and increases channel activity by binding to the cytoplasmic domain and stabilizing the channel in an open conformation (PubMed:19171771). Also contributes to Ca(2+) release from intracellular stores in response to ADP-ribose (PubMed:19454650). Plays a role in numerous processes that involve signaling via intracellular Ca(2+) levels (Probable). Besides, mediates the release of lysosomal Zn(2+) stores in response to reactive oxygen species, leading to increased cytosolic Zn(2+) levels (PubMed:25562606, PubMed:27068538). Activated by moderate heat (35 to 40 degrees Celsius) (PubMed:16601673). Activated by intracellular ADP-ribose, beta-NAD (NAD(+)) and similar compounds, and by oxidative stress caused by reactive oxygen or nitrogen species (PubMed:11960981, PubMed:11385575, PubMed:11509734, PubMed:11804595, PubMed:15561722, PubMed:16601673, PubMed:19171771, PubMed:27383051, PubMed:27068538). The precise physiological activators are under debate; the true, physiological activators may be ADP-ribose and ADP-ribose-2'-phosphate (PubMed:20650899, PubMed:25918360). Activation by ADP-ribose and beta-NAD is strongly increased by moderate heat (35 to 40 degrees Celsius) (PubMed:16601673). Likewise, reactive oxygen species lower the threshold for activation by moderate heat (37 degrees Celsius) (PubMed:22493272). Plays a role in mediating behavorial and physiological responses to moderate heat and thereby contributes to body temperature homeostasis. Plays a role in insulin secretion, a process that requires increased cytoplasmic Ca(2+) levels (By similarity). Required for normal IFNG and cytokine secretion and normal innate immune immunity in response to bacterial infection. Required for normal phagocytosis and cytokine release by macrophages exposed to zymosan (in vitro). Plays a role in dendritic cell differentiation and maturation, and in dendritic cell chemotaxis via its role in regulating cytoplasmic Ca(2+) levels (By similarity). Plays a role in the regulation of the reorganization of the actin cytoskeleton and filopodia formation in response to reactive oxygen species via its role in increasing cytoplasmic Ca(2+) and Zn(2+) levels (PubMed:27068538). Confers susceptibility to cell death following oxidative stress (PubMed:12594222, PubMed:25562606).[UniProtKB:Q91YD4]<ref>PMID:11385575</ref> <ref>PMID:11509734</ref> <ref>PMID:11804595</ref> <ref>PMID:11960981</ref> <ref>PMID:12594222</ref> <ref>PMID:15561722</ref> <ref>PMID:16601673</ref> <ref>PMID:19171771</ref> <ref>PMID:19454650</ref> <ref>PMID:20650899</ref> <ref>PMID:20660597</ref> <ref>PMID:22493272</ref> <ref>PMID:25562606</ref> <ref>PMID:25918360</ref> <ref>PMID:27068538</ref> <ref>PMID:27383051</ref> Isoform 2: Lacks cation channel activity. Does not mediate cation transport in response to oxidative stress or ADP-ribose.<ref>PMID:11960981</ref> Isoform 3: Lacks cation channel activity and negatively regulates the channel activity of isoform 1. Negatively regulates susceptibility to cell death in reposponse to oxidative stress.<ref>PMID:12594222</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca(2+) and ADP ribose (ADPR), an NAD(+)-metabolite produced under oxidative stress and neurodegenerative conditions, suggests a role in neurological disorders. We provide a central concept between triple-site ligand binding and the channel gating of human TRPM2. We show consecutive structural rearrangements and channel activation of TRPM2 induced by binding of ADPR in two indispensable locations, and the binding of Ca(2+) in the transmembrane domain. The 8-Br-cADPR-an antagonist of cADPR-binds only to the MHR1/2 domain and inhibits TRPM2 by stabilizing the channel in an apo-like conformation. We conclude that MHR1/2 acts as a orthostatic ligand-binding site for TRPM2. The NUDT9-H domain binds to a second ADPR to assist channel activation in vertebrates, but not necessary in invertebrates. Our work provides insights into the gating mechanism of human TRPM2 and its pharmacology.
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Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel.,Huang Y, Roth B, Lu W, Du J Elife. 2019 Sep 12;8. pii: 50175. doi: 10.7554/eLife.50175. PMID:31513012<ref>PMID:31513012</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6puu" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</SX>
</SX>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Du, J]]
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[[Category: Du J]]
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[[Category: Huang, Y]]
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[[Category: Huang Y]]
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[[Category: Lu, W]]
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[[Category: Lu W]]
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[[Category: 8-br-cadpr]]
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[[Category: Calcium]]
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[[Category: Transport protein]]
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[[Category: Trpm2 channel]]
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Current revision

Human TRPM2 bound to 8-Br-cADPR and calcium

6puu, resolution 3.70Å

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OCA

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