PDBsum entry 7e2z

Signaling protein

PDB id: 7e2z

Contents

Protein chains

219 a.a.

328 a.a.

45 a.a.

278 a.a.

Ligands

9SC

CLR ×3

J40

PDB id:

7e2z

Name:

Signaling protein

Title:

Aripiprazole-bound serotonin 1a (5-ht1a) receptor-gi protein complex

Structure:

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

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: gnai1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: gnb1. Gene: gng2. Escherichia coli, homo sapiens.

Authors:

P.Xu,S.Huang,H.Zhang,C.Mao,X.E.Zhou,D.D.Shen,Y.Jiang,Y.Zhang,H.E.Xu

Key ref:

P.Xu et al. (2021). Structural insights into the lipid and ligand regulation of serotonin receptors. Nature, 592, 469-473. PubMed id: 33762731 DOI: 10.1038/s41586-021-03376-8

Date:

07-Feb-21 Release date: 14-Apr-21

Protein chain

P63096  (GNAI1_HUMAN) -  Guanine nucleotide-binding protein G(i) subunit alpha-1 from Homo sapiens

Seq: 354 a.a.

Struc: 219 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: 328 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: 45 a.a.

Protein chain

P08908  (5HT1A_HUMAN) -  5-hydroxytryptamine receptor 1A from Homo sapiens

Seq: 422 a.a.

Struc: 278 a.a.*

Protein chain

P0ABE7  (C562_ECOLX) -  Soluble cytochrome b562 from Escherichia coli

Seq: 128 a.a.

Struc: 278 a.a.*

* PDB and UniProt seqs differ at 111 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.3.6.5.- - ?????

DOI no: 10.1038/s41586-021-03376-8

Nature 592:469-473 (2021)

PubMed id: 33762731

Structural insights into the lipid and ligand regulation of serotonin receptors.

P.Xu, S.Huang, H.Zhang, C.Mao, X.E.Zhou, X.Cheng, I.A.Simon, D.D.Shen, H.Y.Yen, C.V.Robinson, K.Harpsøe, B.Svensson, J.Guo, H.Jiang, D.E.Gloriam, K.Melcher, Y.Jiang, Y.Zhang, H.E.Xu.

ABSTRACT

Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter^1,2 that activates the largest subtype family of G-protein-coupled receptors³. Drugs that target 5-HT_1A, 5-HT_1D, 5-HT_1E and other 5-HT receptors are used to treat numerous disorders⁴. 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor-G-protein complexes: 5-HT_1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT_1D bound to 5-HT; and 5-HT_1E in complex with a 5-HT_1E- and 5-HT_1F-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT_1A interface, and is able to increase 5-HT_1A-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules-particularly in the case of 5-HT_1A, in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT_1A are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.