9umx

From Proteopedia

(Difference between revisions)

Current revision

Structure of EP54 bound human C5aR1 in complex with Go

Structural highlights

9umx is a 6 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.C5AR1_HUMAN Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (PubMed:1847994, PubMed:8182049, PubMed:7622471, PubMed:9553099, PubMed:10636859, PubMed:15153520). The ligand interacts with at least two sites on the receptor: a high-affinity site on the extracellular N-terminus, and a second site in the transmembrane region which activates downstream signaling events (PubMed:8182049, PubMed:7622471, PubMed:9553099). Receptor activation stimulates chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production (PubMed:10636859, PubMed:15153520).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

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^[7]

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

References

↑ Christophe T, Rabiet MJ, Tardif M, Milcent MD, Boulay F. Human complement 5a (C5a) anaphylatoxin receptor (CD88) phosphorylation sites and their specific role in receptor phosphorylation and attenuation of G protein-mediated responses. Desensitization of C5a receptor controls superoxide production but not receptor sequestration in HL-60 cells. J Biol Chem. 2000 Jan 21;275(3):1656-64. PMID:10636859
↑ Postma B, Poppelier MJ, van Galen JC, Prossnitz ER, van Strijp JA, de Haas CJ, van Kessel KP. Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor. J Immunol. 2004 Jun 1;172(11):6994-7001. PMID:15153520
↑ Gerard NP, Gerard C. The chemotactic receptor for human C5a anaphylatoxin. Nature. 1991 Feb 14;349(6310):614-7. PMID:1847994 doi:http://dx.doi.org/10.1038/349614a0
↑ Monk PN, Barker MD, Partridge LJ, Pease JE. Mutation of glutamate 199 of the human C5a receptor defines a binding site for ligand distinct from the receptor N terminus. J Biol Chem. 1995 Jul 14;270(28):16625-9. PMID:7622471
↑ DeMartino JA, Van Riper G, Siciliano SJ, Molineaux CJ, Konteatis ZD, Rosen H, Springer MS. The amino terminus of the human C5a receptor is required for high affinity C5a binding and for receptor activation by C5a but not C5a analogs. J Biol Chem. 1994 May 20;269(20):14446-50. PMID:8182049
↑ Chen Z, Zhang X, Gonnella NC, Pellas TC, Boyar WC, Ni F. Residues 21-30 within the extracellular N-terminal region of the C5a receptor represent a binding domain for the C5a anaphylatoxin. J Biol Chem. 1998 Apr 24;273(17):10411-9. PMID:9553099
↑ 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. Molecular fingerprints of a convergent mechanism orchestrating diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptors. bioRxiv [Preprint]. 2025 May 29:2025.05.26.656101. PMID:40501890 doi:10.1101/2025.05.26.656101

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9umx"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9umx is ON HOLD  until Paper Publication
+==Structure of EP54 bound human C5aR1 in complex with Go==
+<StructureSection load='9umx' size='340' side='right'caption='[[9umx]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9umx]] 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=9UMX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9UMX 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]] 3.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DAL:D-ALANINE'>DAL</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=9umx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9umx OCA], [https://pdbe.org/9umx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9umx RCSB], [https://www.ebi.ac.uk/pdbsum/9umx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9umx ProSAT]</span></td></tr>
+</table>
+== Function ==
+[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.[https://www.uniprot.org/uniprot/C5AR1_HUMAN C5AR1_HUMAN] Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (PubMed:1847994, PubMed:8182049, PubMed:7622471, PubMed:9553099, PubMed:10636859, PubMed:15153520). The ligand interacts with at least two sites on the receptor: a high-affinity site on the extracellular N-terminus, and a second site in the transmembrane region which activates downstream signaling events (PubMed:8182049, PubMed:7622471, PubMed:9553099). Receptor activation stimulates chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production (PubMed:10636859, PubMed:15153520).<ref>PMID:10636859</ref> <ref>PMID:15153520</ref> <ref>PMID:1847994</ref> <ref>PMID:7622471</ref> <ref>PMID:8182049</ref> <ref>PMID:9553099</ref>
+<div style="background-color:#fffaf0;">
+== 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.
-Authors: Banerjee, R., Yadav, M.K., Ganguly, M., Mishra, S., Dalal, A., Shukla, A.K.
+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>
-Description: Structure of EP54 bound human C5aR1 in complex with Go
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Ganguly, M]]
+<div class="pdbe-citations 9umx" style="background-color:#fffaf0;"></div>
-[[Category: Yadav, M.K]]
+== References ==
-[[Category: Shukla, A.K]]
+<references/>
-[[Category: Banerjee, R]]
+__TOC__
-[[Category: Mishra, S]]
+</StructureSection>
-[[Category: Dalal, A]]
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Mus musculus]]
+[[Category: Banerjee R]]
+[[Category: Dalal A]]
+[[Category: Ganguly M]]
+[[Category: Mishra S]]
+[[Category: Shukla AK]]
+[[Category: Yadav MK]]

9umx

From Proteopedia

Current revision

Structure of EP54 bound human C5aR1 in complex with Go

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox