9v81: Difference between revisions

Line 1:

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

~~The entry~~ 9v81 is ~~ON HOLD until 2027~~-05-29

==cryoEM structure of HEP-50768-bound MRGPRX4-Gq complex==

== Structural highlights ==

<table><tr><td colspan='2'>[[9v81]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9V81 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9V81 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]] 2.63Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L9Y:5-[2-fluoranyl-3-[(2~{S})-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]phenyl]-1~{H}-1,2,3,4-tetrazole'>A1L9Y</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=9v81 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9v81 OCA], [https://pdbe.org/9v81 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9v81 RCSB], [https://www.ebi.ac.uk/pdbsum/9v81 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9v81 ProSAT]</span></td></tr>

</table>

== Function ==

[https://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.<ref>PMID:18611381</ref>

== Publication Abstract from PubMed ==

Chronic itch, particularly in cholestatic and uremic conditions, poses a notable clinical burden, yet treatment options remain inadequate. MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptor predominantly expressed in human sensory neurons, has emerged as a critical mediator of cholestatic pruritus. Here we identified and characterized HEP-50768, a potent and selective small-molecule inverse agonist of hX4 through high-throughput screening and structure-activity optimization. Structural elucidation through cryo-electron microscopy of the hX4-inverse agonist complex structure revealed the unique binding mode and inhibitory mechanism of HEP-50768. In hX4-humanized rats, HEP-50768 robustly suppressed bile-acid-induced pruritic behaviors. Comprehensive preclinical absorption, distribution, metabolism, excretion and safety profiling was performed in both rats and monkeys, and these findings establish HEP-50768 as a promising therapeutic candidate for chronic itch, supporting its advancement to clinical evaluation.

~~Authors~~:

Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment.,Yang J, Shen R, Wang C, Zhu W, Ke H, Fan J, Zhang M, Liu Y, Li S, Li G, Wang X, Li Y, Cao C, Lei X Nat Chem Biol. 2026 Apr 9. doi: 10.1038/s41589-026-02195-0. PMID:41957282<ref>PMID:41957282</ref>

~~Description~~:

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

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

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Escherichia coli]]

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Mus musculus]]

[[Category: Cao C]]

[[Category: Wang C]]

[[Category: Zhang M]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9v81 is ON HOLD  until 2027-05-29
+==cryoEM structure of HEP-50768-bound MRGPRX4-Gq complex==
+<StructureSection load='9v81' size='340' side='right'caption='[[9v81]], [[Resolution|resolution]] 2.63&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9v81]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9V81 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9V81 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]] 2.63&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L9Y:5-[2-fluoranyl-3-[(2~{S})-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]phenyl]-1~{H}-1,2,3,4-tetrazole'>A1L9Y</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=9v81 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9v81 OCA], [https://pdbe.org/9v81 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9v81 RCSB], [https://www.ebi.ac.uk/pdbsum/9v81 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9v81 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.<ref>PMID:18611381</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Chronic itch, particularly in cholestatic and uremic conditions, poses a notable clinical burden, yet treatment options remain inadequate. MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptor predominantly expressed in human sensory neurons, has emerged as a critical mediator of cholestatic pruritus. Here we identified and characterized HEP-50768, a potent and selective small-molecule inverse agonist of hX4 through high-throughput screening and structure-activity optimization. Structural elucidation through cryo-electron microscopy of the hX4-inverse agonist complex structure revealed the unique binding mode and inhibitory mechanism of HEP-50768. In hX4-humanized rats, HEP-50768 robustly suppressed bile-acid-induced pruritic behaviors. Comprehensive preclinical absorption, distribution, metabolism, excretion and safety profiling was performed in both rats and monkeys, and these findings establish HEP-50768 as a promising therapeutic candidate for chronic itch, supporting its advancement to clinical evaluation.
-Authors:
+Development of a clinically viable MRGPRX4 inverse agonist for cholestatic itch treatment.,Yang J, Shen R, Wang C, Zhu W, Ke H, Fan J, Zhang M, Liu Y, Li S, Li G, Wang X, Li Y, Cao C, Lei X Nat Chem Biol. 2026 Apr 9. doi: 10.1038/s41589-026-02195-0. PMID:41957282<ref>PMID:41957282</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 9v81" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Escherichia coli]]
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Mus musculus]]
+[[Category: Cao C]]
+[[Category: Wang C]]
+[[Category: Zhang M]]