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TitleMolecular insights into atypical modes of β-arrestin interaction with seven transmembrane receptors.
Journal, issue, pagesScience, Vol. 383, Issue 6678, Page 101-108, Year 2024
Publish dateJan 5, 2024
AuthorsJagannath Maharana / Fumiya K Sano / Parishmita Sarma / Manish K Yadav / Longhan Duan / Tomasz M Stepniewski / Madhu Chaturvedi / Ashutosh Ranjan / Vinay Singh / Sayantan Saha / Gargi Mahajan / Mohamed Chami / Wataru Shihoya / Jana Selent / Ka Young Chung / Ramanuj Banerjee / Osamu Nureki / Arun K Shukla /
PubMed Abstractβ-arrestins (βarrs) are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor ...β-arrestins (βarrs) are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor activation and phosphorylation. Here, we present seven cryo-electron microscopy structures of βarrs either in the basal state, activated by the muscarinic receptor subtype 2 (M2R) through its third intracellular loop, or activated by the βarr-biased decoy D6 receptor (D6R). Combined with biochemical, cellular, and biophysical experiments, these structural snapshots allow the visualization of atypical engagement of βarrs with 7TMRs and also reveal a structural transition in the carboxyl terminus of βarr2 from a β strand to an α helix upon activation by D6R. Our study provides previously unanticipated molecular insights into the structural and functional diversity encoded in 7TMR-βarr complexes with direct implications for exploring novel therapeutic avenues.
External linksScience / PubMed:38175886
MethodsEM (single particle)
Resolution2.9 - 6.53 Å
Structure data

EMDB-34174, PDB-8go9:
Structure of beta-arrestin2 in complex with a phosphopeptide corresponding to the human Atypical chemokine receptor 2, ACKR2 (D6R)
Method: EM (single particle) / Resolution: 3.35 Å

EMDB-36078, PDB-8j8r:
Structure of beta-arrestin2 in complex with M2Rpp
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-36081, PDB-8j8v:
Structure of beta-arrestin2 in complex with D6Rpp (Local Refine)
Method: EM (single particle) / Resolution: 3.22 Å

EMDB-36082, PDB-8j8z:
Structure of beta-arrestin1 in complex with D6Rpp
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-36090, PDB-8j97:
Structure of Muscarinic receptor (M2R) in complex with beta-arrestin1 (Local refine, cross-linked)
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-36091: Muscarinic receptor (M2R) in complex with beta-arrestin1 (Low resolution full map, Cross-linked)
Method: EM (single particle) / Resolution: 6.53 Å

EMDB-36093: Muscarinic receptor (M2R) in complex with beta-arrestin1 (Low resolution full map, non-crosslinked)
Method: EM (single particle) / Resolution: 5.4 Å

EMDB-36110, PDB-8j9k:
Structure of basal beta-arrestin2
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-36124, PDB-8ja3:
Structure of beta-arrestin1 in complex with C3aRpp
Method: EM (single particle) / Resolution: 3.94 Å

EMDB-36126, PDB-8jaf:
Structure of Muscarinic receptor (M2R) in complex with beta-arrestin1 (Local Refine, non-cross linked)
Method: EM (single particle) / Resolution: 3.1 Å

Source
  • bos taurus (cattle)
  • mus musculus (house mouse)
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / Arrestin / SIGNALING PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex / SYGNALING PROTEIN/IMMUNE SYSTEM / SYGNALING PROTEIN-IMMUNE SYSTEM complex

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