Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Molecular fingerprints of a convergent mechanism orchestrating diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptors.
Journal, issue, pages	bioRxiv, Year 2025
Publish date	May 29, 2025
Authors	Sudha Mishra / Manish K Yadav / Annu Dalal / Manisankar Ganguly / Ravi Yadav / Kazuhiro Sawada / Divyanshu Tiwari / Nabarun Roy / Nilanjana Banerjee / Jenny N Fung / Jianina Marallag / Cedric S Cui / Xaria X Li / John D Lee / Calvin Aaron Dsouza / Shirsha Saha / Parishmita Sarma / Ganita Rawat / Houming Zhu / Htet A Khant / Richard J Clark / Fumiya K Sano / Ramanuj Banerjee / Trent M Woodruff / Osamu Nureki / Cornelius Gati / Arun K Shukla /
PubMed Abstract	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 ...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 βarr binding and activation using cryo-EM structures. Interestingly, we observe that βarrs 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.
External links	bioRxiv / PubMed:40501890 / PubMed Central
Methods	EM (single particle)
Resolution	2.72 - 3.57 Å
Structure data	62578 9kug EMDB-62578, PDB-9kug: Structure of EP67 bound to human C5aR1 in complex with Go Method: EM (single particle) / Resolution: 3.07 Å 62580 9kut EMDB-62580, PDB-9kut: Structure of JR14a bound to human C3aR in complex with Go Method: EM (single particle) / Resolution: 3.29 Å 62586 9kv6 EMDB-62586, PDB-9kv6: Structure of mouse TLQP21 bound to mouse C3aR in complex with Go Method: EM (single particle) / Resolution: 2.88 Å 62588 9kv8 EMDB-62588, PDB-9kv8: Structure of human TLQP21 bound to mouse C3aR in complex with Go Method: EM (single particle) / Resolution: 3.17 Å 62598 9kvp EMDB-62598, PDB-9kvp: Structure of SB290157 bound to human C3aR in complex with Go (Full map) Method: EM (single particle) / Resolution: 2.79 Å 62610 9kwg EMDB-62610, PDB-9kwg: Structure of mouse C5a bound mouse C5aR1 in complex with Go Method: EM (single particle) / Resolution: 3.15 Å 62619 9kwx EMDB-62619, PDB-9kwx: Structure of mouse C5a-desArg bound mouse C5aR1 in complex with Go Method: EM (single particle) / Resolution: 3.13 Å 62624 9kx6 EMDB-62624, PDB-9kx6: Structure of human C5a-desArg bound mouse C5aR1 in complex with Go Method: EM (single particle) / Resolution: 3.11 Å 62626 9kxs EMDB-62626, PDB-9kxs: Structure of EP67 bound mouse C5aR1 in complex with Go Method: EM (single particle) / Resolution: 3.31 Å 62636 9ky2 EMDB-62636, PDB-9ky2: Structure of beta-arrestin2 in complex with mouse C5aR1pp Method: EM (single particle) / Resolution: 2.78 Å 62649 9kyu EMDB-62649, PDB-9kyu: Structure of beta-arrestin1 in complex with mouse C5aR1pp Method: EM (single particle) / Resolution: 2.72 Å 62651 9kz2 EMDB-62651, PDB-9kz2: Structure of EP67 bound human C3aR in complex with Go Method: EM (single particle) / Resolution: 3.43 Å 62654 9kz8 EMDB-62654, PDB-9kz8: Structure of EP67 bound mouse C3aR in complex with Go Method: EM (single particle) / Resolution: 3.3 Å 62665 9kzk EMDB-62665, PDB-9kzk: Structure of mouse C3a bound mouse C3aR in complex with Go Method: EM (single particle) / Resolution: 3.54 Å 62712 9l0h EMDB-62712, PDB-9l0h: Structure of JR14a bound mouse C3aR in complex with Go Method: EM (single particle) / Resolution: 3.57 Å 64276 9umj EMDB-64276, PDB-9umj: Structure of EP54 bound mouse C3aR in complex with Go Method: EM (single particle) / Resolution: 3.38 Å 64291 9umr EMDB-64291, PDB-9umr: Structure of C5a-pep bound human C5aR1 in complex with Go Method: EM (single particle) / Resolution: 3.15 Å 64325 9umx EMDB-64325, PDB-9umx: Structure of EP54 bound human C5aR1 in complex with Go Method: EM (single particle) / Resolution: 3.2 Å
Chemicals	PDB-1d9a: SOLUTION STRUCTURE OF THE SECOND RNA-BINDING DOMAIN (RBD2) OF HU ANTIGEN C (HUC) PDB-1l6y: Crystal Structure of Porphobilinogen Synthase Complexed with the Inhibitor 4-Oxosebacic Acid
Source	homo sapiens (human) mus musculus (house mouse) bos taurus (domestic cattle) rattus norvegicus (Norway rat)
Keywords	SIGNALING PROTEIN / G protein coupled receptor / G protein / Membrane protein / Immunite system / GPCR / SIGNALING PROTEIN-IMMUNE SYSTEM complex / beta-arrestin