Biology subjects

Barnes, N.

Publications and source records attributed to Barnes, N..

3 recordsLinked to original sources

bioRxiv2025

Structure-guided allosteric modulation of the delta opioid receptor

Opioid analgesics remain essential for pain management but are associated with significant adverse effects, including respiratory depression, tolerance, and dependence. The {delta}-opioid receptor ({delta}OR) represents a promising therapeutic target for developing safer opioid analgesics with reduced adverse effects compared to conventional -opioid receptor-targeting drugs. Positive allosteric modulators (PAMs) offer advantages over direct agonists by enhancing endogenous opioid signaling while preserving natural spatiotemporal activation patterns, potentially avoiding tolerance and dependence issues. Here, we present high-resolution cryo-EM structures of {delta}OR complexed with the peptide agonist DADLE and the PAM MIPS3614, revealing a novel lipid-facing allosteric binding site formed by transmembrane helices 2, 3, and 4. MIPS3614 stabilizes the active receptor conformation through a critical hydrogen bond with residue N1313.35 in the conserved sodium binding site, a key regulatory region controlling GPCR activation. Comprehensive mutagenesis, molecular dynamics simulations, and structure-activity relationships validate this proposed mechanism. Structure-guided optimization yielded MIPS3983 with enhanced binding affinity and retained cooperativity. Our findings establish the first molecular framework for {delta}OR allosteric modulation and provide a structural foundation for the rational design of safer opioid therapeutics.

pharmacology and toxicology↗

bioRxiv2025

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins

Targeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a rapidly emerging therapeutic strategy for difficult-to-drug cytosolic proteins. PROTACs are heterobifunctional small molecules that bridge the target with an E3 ubiquitin ligase, destining it for degradation by the proteasome. They have the potential to be orally available and to act catalytically, switching the pharmacology from occupancy-driven to event-driven (1-3). Here we present a strategy for targeted degradation of extracellular proteins by reshaping the interaction between the broadly expressed lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation with the target and sortilin, followed by endocytosis and lysosomal degradation. SORTAC activity can be genetically encoded as demonstrated by converting an IgG binding nanobody to an IgG degrading nanobody or by chemical conjugation, enabling single step conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, using structure-based design, we generated small molecule SORTACs against the inflammatory cytokine TNFa with nanomolar range potency and with physicochemical properties like PROTACs. Our results demonstrate that SORTACs constitute a versatile and highly modular platform for rapid generation of degraders of in theory any extracellular target and with the potential to have wide impact in drug discovery.

biochemistry↗

bioRxiv2025

Recolonisation strategies of early animals in the Avalon (Ediacaran 574 - 560 Ma)

The first geographically widespread metazoans are found in the Avalon assemblage (Ediacaran; 574 - 560 Ma). These early animals were regularly disturbed by sedimentation events such as ash flows and turbidites, leading to an apparent "resetting" of communities. However, it is not clear how biological legacies - remains or survivors of disturbance events - influenced community ecology in the Avalon. Here, we use spatial point process analysis on 19 Avalon palaeocommunities to test whether two forms of biological legacy (fragmentary remains of Fractofusus and surviving frondomorphs) impacted the recolonisation dynamics of Avalon palaeocommunities. We found that densities of Fractofusus were increased around the Fractofusus fragments, suggesting that they helped to recolonise the post-disturbance substrate, potentially contributing to the Fractofusus dominance found in 8 of the 19 palaeocommunities. However, we found no such effects for survivor fronds. Our results suggest that the evolution of height was for long-distance dispersal rather than local recolonisation. In modern deep-sea environments, there is a trade-off between local and long-distance dispersal, and our work demonstrates that this differentiation of reproductive strategies had already developed in the early animals of the Avalon.

ecology↗