PDBsum entry 6u1n

Signaling protein/immune system

PDB id: 6u1n

Contents

Protein chains

278 a.a.

359 a.a.

119 a.a.

108 a.a.

Ligands

2CU

PDB id:

6u1n

Name:

Signaling protein/immune system

Title:

Gpcr-beta arrestin structure in lipid bilayer

Structure:

Muscarinic acetylcholine receptor m2, vasopressin v2 receptor chimera. Chain: r. Fragment: m2 unp residues 2-466 + v2 unp residues 343-371. Synonym: v2r, avpr v2, antidiuretic hormone receptor, renal-type arginine vasopressin receptor. Engineered: yes. Beta-arrestin-1. Chain: c.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: chrm2, avpr2, adhr, dir, dir3, v2r. Expressed in: homo sapiens. Expression_system_taxid: 9606. Rattus norvegicus. Rat. Organism_taxid: 10116.

Authors:

D.P.Staus,H.Hu,M.J.Robertson,A.L.W.Kleinhenz,L.M.Wingler,W.D.Capel, N.R.Latorraca,R.J.Lefkowitz,G.Skiniotis

Key ref:

D.P.Staus et al. (2020). Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc. Nature, 579, 297-302. PubMed id: 31945772 DOI: 10.1038/s41586-020-1954-0

Date:

16-Aug-19 Release date: 26-Feb-20

Protein chain

P08172  (ACM2_HUMAN) -  Muscarinic acetylcholine receptor M2 from Homo sapiens

Seq: 466 a.a.

Struc: 278 a.a.*

Protein chain

P30518  (V2R_HUMAN) -  Vasopressin V2 receptor from Homo sapiens

Seq: 371 a.a.

Struc: 278 a.a.*

Protein chain

P29066  (ARRB1_RAT) -  Beta-arrestin-1 from Rattus norvegicus

Seq: 418 a.a.

Struc: 359 a.a.*

Protein chain

V9HW68  (V9HW68_HUMAN) -  Epididymis luminal protein 214 from Homo sapiens

Seq: 470 a.a.

Struc: 119 a.a.*

Protein chain

Q7Z3Y4  (Q7Z3Y4_HUMAN) -  Ig-like domain-containing protein from Homo sapiens

Seq: 236 a.a.

Struc: 108 a.a.*

* PDB and UniProt seqs differ at 268 residue positions (black crosses)

DOI no: 10.1038/s41586-020-1954-0

Nature 579:297-302 (2020)

PubMed id: 31945772

Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc.

D.P.Staus, H.Hu, M.J.Robertson, A.L.W.Kleinhenz, L.M.Wingler, W.D.Capel, N.R.Latorraca, R.J.Lefkowitz, G.Skiniotis.

ABSTRACT

After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis¹. Additionally, β-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins². In contrast to G proteins, for which there are many high-resolution structures in complex with GPCRs, the molecular mechanisms underlying the interaction of β-arrestin with GPCRs are much less understood. Here we present a cryo-electron microscopy structure of β-arrestin 1 (βarr1) in complex with M2 muscarinic receptor (M2R) reconstituted in lipid nanodiscs. The M2R-βarr1 complex displays a multimodal network of flexible interactions, including binding of the N domain of βarr1 to phosphorylated receptor residues and insertion of the finger loop of βarr1 into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric G_o protein complex³. Moreover, the cryo-electron microscopy map reveals that the C-edge of βarr1 engages the lipid bilayer. Through atomistic simulations and biophysical, biochemical and cellular assays, we show that the C-edge is critical for stable complex formation, βarr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest that the cooperative interactions of β-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility.