Structure and dynamics of dynorphin peptide and its receptor

Abstract

Dynorphin is a neuropeptide involved in pain, addiction and mood regulation. It exerts its activity by binding to the kappa opioid receptor (KOP) which belongs to the large family of G-protein coupled receptors. The dynorphin peptide was discovered in 1975, while its receptor was cloned in 1993. This review will describe: a) the activities and physiological functions of dynorphin and its receptor, b) early structure-activity relationship studies performed before cloning of the receptor (mostly pharmacological and biophysical studies of peptide analogues), c) structureactivity relationship studies performed after cloning of the receptor via receptor mutagenesis and the development of recombinant receptor expression systems, d) structural biology of the opiate receptors culminating in X-ray structures of the four opioid receptors in their inactive state and structures of MOP and KOP receptors in their active state. X-ray and EM structures are combined with NMR data, which gives complementary insight into receptor and peptide dynamics.Molecular modelling greatly benefited from the availability of atomic resolution 3D structures of receptor-ligand complexes and an example of the strategy used to model a dynorphin-KOP receptor complex using NMR data will be described. These achievements have led to a better understanding of the complex dynamics of KOP receptor activation and to the development of new ligands and drugs.

High-throughput characterization of photocrosslinker-bearing ion channel variants to map residues critical for function and pharmacology

“…This represents a notable advantage, especially for highly state-dependent interactions, such as those between hASIC1a and BigDyn or PcTx1. Additionally, comparing the crosslinking pattern between two ligands, the approach can indirectly inform on the varying degrees of conformational flexibility of the ligands: BigDyn is likely to be highly flexible without a strong propensity to adopt a secondary fold (O’Connor et al ., 2015; Ferre et al ., 2019) and therefore samples a greater conformational space and is thus more likely to undergo covalent crosslinking at multiple sites (9/9 sites tested at the acidic pocket, (Borg et al ., 2020)). By contrast, PcTx1 folds into a compact and highly stable conformation and will consequently undergo covalent crosslinking at relatively fewer sites (4/9 sites tested at the acidic pocket, Figure 5).…”

“…BigDyn is likely to be highly flexible without a strong propensity to adopt a secondary fold (O'Connor et al, 2015;Ferre et al, 2019) and therefore samples a greater conformational space and is thus more likely to undergo covalent crosslinking at multiple sites (9/9 sites tested at the acidic pocket, (Borg et al, 2020)). By contrast, PcTx1 folds into a compact and highly stable conformation and will consequently undergo covalent crosslinking at relatively fewer sites (4/9 sites tested at the acidic pocket, Figure 5).…”

High-throughput characterization of photocrosslinker-bearing ion channel variants to map residues critical for function and pharmacology

“…This represents a notable advantage, especially for highly state-dependent interactions, such as those between hASIC1a and BigDyn or PcTx1. Additionally, comparing the crosslinking pattern between 2 ligands, the approach can indirectly inform on the varying degrees of conformational flexibility of the ligands: BigDyn is likely to be highly flexible without a strong propensity to adopt a secondary fold [68,69], therefore samples a greater conformational space and is thus more likely to undergo covalent crosslinking at multiple sites (9/9 sites tested at the acidic pocket [17]). By contrast, PcTx1 folds into a compact and highly stable conformation and will consequently undergo covalent crosslinking at relatively fewer sites (4/ 9 sites tested at the acidic pocket; Fig 5).…”

Mechanism and site of action of big dynorphin on ASIC1a

“…Trp7 and Trp24 in PcTx1 (31) and Tyr1 in BigDyn). However, the binding mode is likely to differ substantially between the two peptides, as PcTx1 adopts a rigid fold, while BigDyn is likely unstructured in aqueous solution (44,45). Indeed, the two peptides have opposite modulatory effects on ASIC1a:…”