8feg
From Proteopedia
CryoEM structure of Kappa Opioid Receptor bound to a semi-peptide and Gi1
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedDespite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-beta-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies demonstrate that DNCP-beta-NalA(1) induces a potent KOR-mediated antinociception in male mice. The high-resolution cryo-EM structure (2.6 A) of the DNCP-beta-NalA-KOR-Gi1 complex and molecular dynamics simulations are harnessed to validate the computational design model. This reveals a network of residues in ECL2/3 and TM6/7 controlling the intrinsic efficacy of KOR. In general, our computational de novo platform overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may drive the development of next-generation therapeutics for medical applications such as pain conditions. Design and structural validation of peptide-drug conjugate ligands of the kappa-opioid receptor.,Muratspahic E, Deibler K, Han J, Tomasevic N, Jadhav KB, Olive-Marti AL, Hochrainer N, Hellinger R, Koehbach J, Fay JF, Rahman MH, Hegazy L, Craven TW, Varga BR, Bhardwaj G, Appourchaux K, Majumdar S, Muttenthaler M, Hosseinzadeh P, Craik DJ, Spetea M, Che T, Baker D, Gruber CW Nat Commun. 2023 Dec 6;14(1):8064. doi: 10.1038/s41467-023-43718-w. PMID:38052802[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
|
| |||||||||||||||||||
