PDBsum entry 4jqi

Signaling protein

PDB id: 4jqi

Contents

Protein chains

353 a.a.

204 a.a.

185 a.a.

21 a.a.

Ligands

EDO ×6

PRO

Metals

_CL ×2

Waters ×108

PDB id:

4jqi

Name:

Signaling protein

Title:

Structure of active beta-arrestin1 bound to a g protein-coupled receptor phosphopeptide

Structure:

Beta-arrestin-1. Chain: a. Synonym: arrestin beta-1. Engineered: yes. Fab30 heavy chain. Chain: h. Engineered: yes. Fab30 light chain. Chain: l.

Source:

Rattus norvegicus. Brown rat,rat,rats. Organism_taxid: 10116. Gene: arrb1. Expressed in: escherichia coli. Expression_system_taxid: 562. Mus musculus. Organism_taxid: 10090. Synthetic: yes

Resolution:

2.60Å R-factor: 0.203 R-free: 0.247

Authors:

A.K.Shukla,A.Manglik,A.C.Kruse,K.Xiao,R.I.Reis,W.C.Tseng,D.P.Staus, D.Hilger,S.Uysal,L.H.Huang,M.Paduch,P.T.Shukla,A.Koide,S.Koide, W.I.Weis,A.A.Kossiakoff,B.K.Kobilka,R.J.Lefkowitz

Key ref:

A.K.Shukla et al. (2013). Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature, 497, 137-141. PubMed id: 23604254 DOI: 10.1038/nature12120

Date:

20-Mar-13 Release date: 17-Apr-13

Protein chain

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

Seq: 418 a.a.

Struc: 353 a.a.

Protein chain

No UniProt id for this chain

Struc: 204 a.a.

Protein chain

No UniProt id for this chain

Struc: 185 a.a.

Protein chain

P30518  (V2R_HUMAN) -  Vasopressin V2 receptor from Homo sapiens

Seq: 371 a.a.

Struc: 21 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DOI no: 10.1038/nature12120

Nature 497:137-141 (2013)

PubMed id: 23604254

Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide.

A.K.Shukla, A.Manglik, A.C.Kruse, K.Xiao, R.I.Reis, W.C.Tseng, D.P.Staus, D.Hilger, S.Uysal, L.Y.Huang, M.Paduch, P.Tripathi-Shukla, A.Koide, S.Koide, W.I.Weis, A.A.Kossiakoff, B.K.Kobilka, R.J.Lefkowitz.

ABSTRACT

The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors, and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization. Arrestins activated by interaction with phosphorylated receptors can also mediate G-protein-independent signalling by serving as adaptors to link receptors to numerous signalling pathways. Despite their central role in regulation and signalling of GPCRs, a structural understanding of β-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of β-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide has previously been shown to functionally and conformationally activate β-arrestin-1 (ref. 5). To capture this active conformation, we used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of β-arrestin-1. The structure of the β-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in β-arrestin-1 compared to its inactive conformation. These include rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of β-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on β-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins.