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TitleEngineered odorant receptors illuminate the basis of odour discrimination.
Journal, issue, pagesNature, Year 2024
Publish dateOct 30, 2024
AuthorsClaire A de March / Ning Ma / Christian B Billesbølle / Jeevan Tewari / Claudia Llinas Del Torrent / Wijnand J C van der Velden / Ichie Ojiro / Ikumi Takayama / Bryan Faust / Linus Li / Nagarajan Vaidehi / Aashish Manglik / Hiroaki Matsunami /
PubMed AbstractHow the olfactory system detects and distinguishes odorants with diverse physicochemical properties and molecular configurations remains poorly understood. Vertebrate animals perceive odours through ...How the olfactory system detects and distinguishes odorants with diverse physicochemical properties and molecular configurations remains poorly understood. Vertebrate animals perceive odours through G protein-coupled odorant receptors (ORs). In humans, around 400 ORs enable the sense of smell. The OR family comprises two main classes: class I ORs are tuned to carboxylic acids whereas class II ORs, which represent most of the human repertoire, respond to a wide variety of odorants. A fundamental challenge in understanding olfaction is the inability to visualize odorant binding to ORs. Here we uncover molecular properties of odorant-OR interactions by using engineered ORs crafted using a consensus protein design strategy. Because such consensus ORs (consORs) are derived from the 17 major subfamilies of human ORs, they provide a template for modelling individual native ORs with high sequence and structural homology. The biochemical tractability of consORs enabled the determination of four cryogenic electron microscopy structures of distinct consORs with specific ligand recognition properties. The structure of a class I consOR, consOR51, showed high structural similarity to the native human receptor OR51E2 and generated a homology model of a related member of the human OR51 family with high predictive power. Structures of three class II consORs revealed distinct modes of odorant-binding and activation mechanisms between class I and class II ORs. Thus, the structures of consORs lay the groundwork for understanding molecular recognition of odorants by the OR superfamily.
External linksNature / PubMed:39478229
MethodsEM (single particle)
Resolution3.2 - 3.62 Å
Structure data

EMDB-42786, PDB-8uxv:
Consensus olfactory receptor consOR51 in complex with mini-Gs trimeric protein
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-42789, PDB-8uxy:
Consensus olfactory receptor consOR1 bound to L-menthol and in complex with mini-Gs trimeric protein
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-42791, PDB-8uy0:
Consensus olfactory receptor consOR2 bound to S-carvone and in complex with mini-Gs trimeric protein
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-42817, PDB-8uyq:
Consensus olfactory receptor consOR4 bound to 2-methylthiazoline and in complex with mini-Gs trimeric protein
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-45880: Consensus olfactory receptor consOR4 bound to 2-methylthiazoline and in complex with mini-Gs trimeric protein (transmembrane domain)
Method: EM (single particle) / Resolution: 3.62 Å

Chemicals


ChemComp, No image

ChemComp-XUQ:
Unknown entry

ChemComp-0WU:
(5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-one


ChemComp, No image

ChemComp-XVT:
Unknown entry

Source
  • synthetic construct (others)
  • lama glama (llama)
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Odorant / Olfaction / GPCR / Receptor

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