8qot
From Proteopedia
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The mu-opioid receptor (muOR), a prototypical member of the G protein-coupled receptor (GPCR) family, is the molecular target of opioid analgesics such as morphine and fentanyl. Due to the limitations and severe side effects of currently available opioid drugs, there is considerable interest in developing novel modulators of muOR function. Most GPCR ligands today are small molecules, however biologics, including antibodies and nanobodies, are emerging as alternative therapeutics with clear advantages such as affinity and target selectivity. Here, we describe the nanobody NbE, which selectively binds to the muOR and acts as an antagonist. We functionally characterize NbE as an extracellular and genetically encoded muOR ligand and uncover the molecular basis for muOR antagonism by solving the cryo-EM structure of the NbE-muOR complex. NbE displays a unique ligand binding mode and achieves muOR selectivity by interactions with the orthosteric pocket and extracellular receptor loops. Based on a beta-hairpin loop formed by NbE that deeply inserts into the muOR and centers most binding contacts, we design short peptide analogues that retain muOR antagonism. The work illustrates the potential of nanobodies to uniquely engage with GPCRs and describes novel muOR ligands that can serve as a basis for therapeutic developments. | The mu-opioid receptor (muOR), a prototypical member of the G protein-coupled receptor (GPCR) family, is the molecular target of opioid analgesics such as morphine and fentanyl. Due to the limitations and severe side effects of currently available opioid drugs, there is considerable interest in developing novel modulators of muOR function. Most GPCR ligands today are small molecules, however biologics, including antibodies and nanobodies, are emerging as alternative therapeutics with clear advantages such as affinity and target selectivity. Here, we describe the nanobody NbE, which selectively binds to the muOR and acts as an antagonist. We functionally characterize NbE as an extracellular and genetically encoded muOR ligand and uncover the molecular basis for muOR antagonism by solving the cryo-EM structure of the NbE-muOR complex. NbE displays a unique ligand binding mode and achieves muOR selectivity by interactions with the orthosteric pocket and extracellular receptor loops. Based on a beta-hairpin loop formed by NbE that deeply inserts into the muOR and centers most binding contacts, we design short peptide analogues that retain muOR antagonism. The work illustrates the potential of nanobodies to uniquely engage with GPCRs and describes novel muOR ligands that can serve as a basis for therapeutic developments. | ||
| - | Structural Basis of mu-Opioid Receptor-Targeting by a Nanobody Antagonist.,Yu J, Kumar A, Zhang X, Martin C, Raia P, Koehl A, Laeremans T, Steyaert J, Manglik A, Ballet S, Boland A, Stoeber M bioRxiv. 2023 Dec 7:2023.12.06.570395. doi: 10.1101/2023.12.06.570395 | + | Structural Basis of mu-Opioid Receptor-Targeting by a Nanobody Antagonist.,Yu J, Kumar A, Zhang X, Martin C, Raia P, Koehl A, Laeremans T, Steyaert J, Manglik A, Ballet S, Boland A, Stoeber M bioRxiv [Preprint]. 2023 Dec 7:2023.12.06.570395. doi: 10.1101/2023.12.06.570395. PMID:38106026<ref>PMID:38106026</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Structure of the mu opioid receptor bound to the antagonist nanobody NbE
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Categories: Lama glama | Large Structures | Mus musculus | Synthetic construct | Ballet S | Boland A | Kumar A | Manglik A | Martin C | Raia P | Stoeber M | Yu J | Zhang X
