PDBsum entry 6d9h

Signaling protein

PDB id: 6d9h

Contents

Protein chains

209 a.a.

338 a.a.

57 a.a.

288 a.a.

Ligands

ADN

PDB id:

6d9h

Name:

Signaling protein

Title:

Cryo-em structure of the human adenosine a1 receptor-gi2-protein complex bound to its endogenous agonist

Structure:

Guanine nucleotide-binding protein g(i) subunit alpha-2. Chain: a. Synonym: adenylate cyclase-inhibiting g alpha protein. Engineered: yes. Guanine nucleotide-binding protein g(i)/g(s)/g(t) subunit beta-1. Chain: b. Synonym: transducin beta chain 1. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: gnai2, gnai2b. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Gene: gnb1. Gene: gng2. Gene: chrm4, adora1.

Authors:

C.J.Draper-Joyce,M.Khoshouei,D.M.Thal,Y.-L.Liang,A.T.N.Nguyen, S.G.B.Furness,H.Venugopal,J.Baltos,J.M.Plitzko,R.Danev,W.Baumeister, L.T.May,D.Wootten,P.Sexton,A.Glukhova,A.Christopoulos

Key ref:

C.J.Draper-Joyce et al. (2018). Structure of the adenosine-bound human adenosine A₁ receptor-G_i complex. Nature, 558, 559-563. PubMed id: 29925945 DOI: 10.1038/s41586-018-0236-6

Date:

29-Apr-18 Release date: 20-Jun-18

Protein chain

P04899  (GNAI2_HUMAN) -  Guanine nucleotide-binding protein G(i) subunit alpha-2 from Homo sapiens

Seq: 355 a.a.

Struc: 209 a.a.*

Protein chain

P62873  (GBB1_HUMAN) -  Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 from Homo sapiens

Seq: 340 a.a.

Struc: 338 a.a.

Protein chain

P59768  (GBG2_HUMAN) -  Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 from Homo sapiens

Seq: 71 a.a.

Struc: 57 a.a.

Protein chain

P08173  (ACM4_HUMAN) -  Muscarinic acetylcholine receptor M4 from Homo sapiens

Seq: 479 a.a.

Struc: 288 a.a.*

Protein chain

P30542  (AA1R_HUMAN) -  Adenosine receptor A1 from Homo sapiens

Seq: 326 a.a.

Struc: 288 a.a.

* PDB and UniProt seqs differ at 267 residue positions (black crosses)

DOI no: 10.1038/s41586-018-0236-6

Nature 558:559-563 (2018)

PubMed id: 29925945

Structure of the adenosine-bound human adenosine A₁ receptor-G_i complex.

C.J.Draper-Joyce, M.Khoshouei, D.M.Thal, Y.L.Liang, A.T.N.Nguyen, S.G.B.Furness, H.Venugopal, J.A.Baltos, J.M.Plitzko, R.Danev, W.Baumeister, L.T.May, D.Wootten, P.M.Sexton, A.Glukhova, A.Christopoulos.

ABSTRACT

The class A adenosine A₁ receptor (A₁R) is a G-protein-coupled receptor that preferentially couples to inhibitory G_i/o heterotrimeric G proteins, has been implicated in numerous diseases, yet remains poorly targeted. Here we report the 3.6 Å structure of the human A₁R in complex with adenosine and heterotrimeric G_i2 protein determined by Volta phase plate cryo-electron microscopy. Compared to inactive A₁R, there is contraction at the extracellular surface in the orthosteric binding site mediated via movement of transmembrane domains 1 and 2. At the intracellular surface, the G protein engages the A₁R primarily via amino acids in the C terminus of the Gα_i α5-helix, concomitant with a 10.5 Å outward movement of the A₁R transmembrane domain 6. Comparison with the agonist-bound β₂ adrenergic receptor-G_s-protein complex reveals distinct orientations for each G-protein subtype upon engagement with its receptor. This active A₁R structure provides molecular insights into receptor and G-protein selectivity.