View source for 9kv8


==Structure of human TLQP21 bound to mouse C3aR in complex with Go==
<StructureSection load='9kv8' size='340' side='right'caption='[[9kv8]], [[Resolution|resolution]] 3.17&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9kv8]] is a 6 chain structure with sequence from [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=9KV8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9KV8 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]] 3.17&#8491;</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=9kv8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9kv8 OCA], [https://pdbe.org/9kv8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9kv8 RCSB], [https://www.ebi.ac.uk/pdbsum/9kv8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9kv8 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/C3AR_MOUSE C3AR_MOUSE] Receptor for the chemotactic and inflammatory peptide anaphylatoxin C3a. This receptor stimulates chemotaxis, granule enzyme release and superoxide anion production.[https://www.uniprot.org/uniprot/ACM4_HUMAN ACM4_HUMAN] The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is inhibition of adenylate cyclase.
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== Publication Abstract from PubMed ==
Complement anaphylatoxin receptors (C3aR and C5aR1) are prototypical G protein-coupled receptors (GPCRs) playing crucial physiological roles in innate immunity by combating pathogenic infections and orchestrating inflammatory responses. They continue to be important therapeutic targets for multiple disorders including autoimmune diseases, acute and chronic inflammation, and allergy-related conditions. Recent structural coverage has provided important insights into their activation and signaling, however, confounding observations in the literature related to ligand efficacy and functional responses, especially in different model systems, present a major challenge for drug discovery efforts. Here, we systematically and comprehensively profile a broad set of natural and synthetic ligands at C3aR and C5aR1 and discover a previously unanticipated level of functional specialization in terms of species-specific pharmacology and receptor activation. Taking a lead from this, we determine seventeen cryo-EM structures of different ligand-receptor-G-protein complexes and uncover distinct orientation of agonists between the human and mouse receptors despite an overlapping positioning in the orthosteric binding pocket. Combined with extensive mutagenesis and functional assays, these structural snapshots allow us to decode and validate a convergent molecular mechanism involving a "Five-Point-Switch" in these receptors that orchestrates the recognition and efficacy of diverse agonists. We also identify species-specific differences at the level of phosphorylation patterns encoded in the carboxyl-terminus of these receptors and directly visualize their impact on betaarr binding and activation using cryo-EM structures. Interestingly, we observe that betaarrs engage with the mouse C5aR1 using a variation of previously discovered P-X-P-P phosphorylation motif via a "Sliding-Mechanism" and also exhibit distinct oligomeric state for the human vs. mouse receptors. Taken together, this study elucidates functional specialization at the complement anaphylatoxin receptors and underlying molecular mechanisms, offering a previously lacking framework with direct and immediate implications for the development of novel therapeutics.

Molecular fingerprints of a convergent mechanism orchestrating diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptors.,Mishra S, Yadav MK, Dalal A, Ganguly M, Yadav R, Sawada K, Tiwari D, Roy N, Banerjee N, Fung JN, Marallag J, Cui CS, Li XX, Lee JD, Dsouza CA, Saha S, Sarma P, Rawat G, Zhu H, Khant HA, Clark RJ, Sano FK, Banerjee R, Woodruff TM, Nureki O, Gati C, Shukla AK bioRxiv [Preprint]. 2025 May 29:2025.05.26.656101. doi: , 10.1101/2025.05.26.656101. PMID:40501890<ref>PMID:40501890</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Banerjee R]]
[[Category: Dalal A]]
[[Category: Ganguly M]]
[[Category: Gati C]]
[[Category: Mishra S]]
[[Category: Shukla AK]]
[[Category: Yadav MK]]
[[Category: Yadav R]]