PDBsum entry 6vcb

Signaling protein/membrane protein

PDB id: 6vcb

Contents

Protein chains

378 a.a.

31 a.a.

223 a.a.

339 a.a.

59 a.a.

128 a.a.

Ligands

QW7

PDB id:

6vcb

Name:

Signaling protein/membrane protein

Title:

Cryo-em structure of the glucagon-like peptide-1 receptor in complex with g protein, glp-1 peptide and a positive allosteric modulator

Structure:

Glucagon-like peptide 1 receptor. Chain: r. Synonym: glp-1r. Engineered: yes. Glucagon-like peptide 1. Chain: p. Engineered: yes. Guanine nucleotide-binding protein g(s) subunit alpha isoforms short.

Source:

Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Gene: gnas, gnas1, gsp. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: gnb1. Gene: gng2.

Authors:

B.Sun,D.Feng,A.Bueno,B.Kobilka,K.Sloop

Key ref:

A.B.Bueno et al. (2020). Structural insights into probe-dependent positive allosterism of the GLP-1 receptor. Nat Chem Biol, 16, 1105-1110. PubMed id: 32690941 DOI: 10.1038/s41589-020-0589-7

Date:

20-Dec-19 Release date: 22-Jul-20

Protein chain

P43220  (GLP1R_HUMAN) -  Glucagon-like peptide 1 receptor from Homo sapiens

Seq: 463 a.a.

Struc: 378 a.a.*

Protein chain

P01275  (GLUC_HUMAN) -  Pro-glucagon from Homo sapiens

Seq: 180 a.a.

Struc: 31 a.a.

Protein chain

P63092  (GNAS2_HUMAN) -  Guanine nucleotide-binding protein G(s) subunit alpha isoforms short from Homo sapiens

Seq: 394 a.a.

Struc: 223 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: 339 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: 59 a.a.

Protein chain

No UniProt id for this chain

Struc: 128 a.a.

* PDB and UniProt seqs differ at 46 residue positions (black crosses)

Enzyme reactions

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

DOI no: 10.1038/s41589-020-0589-7

Nat Chem Biol 16:1105-1110 (2020)

PubMed id: 32690941

Structural insights into probe-dependent positive allosterism of the GLP-1 receptor.

A.B.Bueno, B.Sun, F.S.Willard, D.Feng, J.D.Ho, D.B.Wainscott, A.D.Showalter, M.Vieth, Q.Chen, C.Stutsman, B.Chau, J.Ficorilli, F.J.Agejas, G.R.Cumming, A.Jiménez, I.Rojo, T.S.Kobilka, B.K.Kobilka, K.W.Sloop.

ABSTRACT

Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a 'molecular glue'. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of GLP-1(7-36). The compound enhances insulin secretion in a glucose-, ligand- and GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric G_s. The modulator binds high in the helical bundle at an interface between TM1 and TM2, allowing access to the peptide ligand. Pharmacological characterization showed strong probe dependence of LSN3160440 for GLP-1(9-36) versus oxyntomodulin that is driven by a single residue. Our findings expand protein-protein modulation drug discovery to uncompetitive, active state stabilizers for peptide hormone receptors.