7BPH

Crystal structure of GppNHp-bound GNAS in complex with the cyclic peptide inhibitor GN13

Summary for 7BPH

• Entry DOI: 10.2210/pdb7bph/pdb
• Related PRD ID: PRD_002362
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, GN13, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total)
• Functional Keywords: g protein, gnas, adenylyl cyclase, active state, inhibitor, mrna display, rapid, cyclic peptide, gsin-1, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 46397.79

Authors

Hu, Q.,Dai, S.,Shokat, K.M. (deposition date: 2020-03-22, release date: 2021-03-31, Last modification date: 2024-11-13)

Primary citation

Dai, S.A.,Hu, Q.,Gao, R.,Blythe, E.E.,Touhara, K.K.,Peacock, H.,Zhang, Z.,von Zastrow, M.,Suga, H.,Shokat, K.M.
State-selective modulation of heterotrimeric G alpha s signaling with macrocyclic peptides.
Cell, 2022

PubMed Abstract: The G protein-coupled receptor cascade leading to production of the second messenger cAMP is replete with pharmacologically targetable proteins, with the exception of the Gα subunit, Gαs. GTPases remain largely undruggable given the difficulty of displacing high-affinity guanine nucleotides and the lack of other drug binding sites. We explored a chemical library of 10 cyclic peptides to expand the chemical search for inhibitors of this enzyme class. We identified two macrocyclic peptides, GN13 and GD20, that antagonize the active and inactive states of Gαs, respectively. Both macrocyclic peptides fine-tune Gαs activity with high nucleotide-binding-state selectivity and G protein class-specificity. Co-crystal structures reveal that GN13 and GD20 distinguish the conformational differences within the switch II/α3 pocket. Cell-permeable analogs of GN13 and GD20 modulate Gαs/Gβγ signaling in cells through binding to crystallographically defined pockets. The discovery of cyclic peptide inhibitors targeting Gαs provides a path for further development of state-dependent GTPase inhibitors.

PubMed: 36170854
DOI: 10.1016/j.cell.2022.09.019

Experimental method

X-RAY DIFFRACTION (1.57 Å)