6lpb

Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein

Structural highlights

6lpb is a 6 chain structure with sequence from Bos taurus, Homo sapiens, Rattus norvegicus and Unidentified. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.9Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PACA_HUMAN Binding to its receptor activates G proteins and stimulates adenylate cyclase in pituitary cells.^[1]

Publication Abstract from PubMed

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide hormone. The PACAP receptor PAC1R, which belongs to the class B G-protein-coupled receptors (GPCRs), is a drug target for mental disorders and dry eye syndrome. Here, we present a cryo-EM structure of human PAC1R bound to PACAP and an engineered Gs heterotrimer. The structure revealed that transmembrane helix TM1 plays an essential role in PACAP recognition. The extracellular domain (ECD) of PAC1R tilts by ~40 degrees compared with that of the glucagon-like peptide-1 receptor (GLP-1R) and thus does not cover the peptide ligand. A functional analysis demonstrated that the PAC1R ECD functions as an affinity trap and is not required for receptor activation, whereas the GLP-1R ECD plays an indispensable role in receptor activation, illuminating the functional diversity of the ECDs in class B GPCRs. Our structural information will facilitate the design and improvement of better PAC1R agonists for clinical applications.

Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein.,Kobayashi K, Shihoya W, Nishizawa T, Kadji FMN, Aoki J, Inoue A, Nureki O Nat Struct Mol Biol. 2020 Mar;27(3):274-280. doi: 10.1038/s41594-020-0386-8. Epub, 2020 Mar 9. PMID:32157248^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Inooka H, Ohtaki T, Kitahara O, Ikegami T, Endo S, Kitada C, Ogi K, Onda H, Fujino M, Shirakawa M. Conformation of a peptide ligand bound to its G-protein coupled receptor. Nat Struct Biol. 2001 Feb;8(2):161-5. PMID:11175907 doi:https://dx.doi.org/10.1038/84159
↑ Kobayashi K, Shihoya W, Nishizawa T, Kadji FMN, Aoki J, Inoue A, Nureki O. Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein. Nat Struct Mol Biol. 2020 Mar;27(3):274-280. doi: 10.1038/s41594-020-0386-8. Epub, 2020 Mar 9. PMID:32157248 doi:https://dx.doi.org/10.1038/s41594-020-0386-8

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OCA

[1] Inooka H, Ohtaki T, Kitahara O, Ikegami T, Endo S, Kitada C, Ogi K, Onda H, Fujino M, Shirakawa M. Conformation of a peptide ligand bound to its G-protein coupled receptor. Nat Struct Biol. 2001 Feb;8(2):161-5. PMID:11175907 doi:https://dx.doi.org/10.1038/84159

[2] Kobayashi K, Shihoya W, Nishizawa T, Kadji FMN, Aoki J, Inoue A, Nureki O. Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein. Nat Struct Mol Biol. 2020 Mar;27(3):274-280. doi: 10.1038/s41594-020-0386-8. Epub, 2020 Mar 9. PMID:32157248 doi:https://dx.doi.org/10.1038/s41594-020-0386-8

[1]

[2]

6lpb

Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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