Engineered odorant receptors illuminate the basis of odour discrimination

Claire A. March (), Ning Ma, Christian B. Billesbølle, Jeevan Tewari, Claudia Llinas del Torrent, Wijnand J. C. Velden, Ichie Ojiro, Ikumi Takayama, Bryan Faust, Linus Li, Nagarajan Vaidehi (), Aashish Manglik () and Hiroaki Matsunami ()
Additional contact information
Claire A. March: Duke University
Ning Ma: Beckman Research Institute of the City of Hope
Christian B. Billesbølle: University of California, San Francisco
Jeevan Tewari: Duke University
Claudia Llinas del Torrent: University of California, San Francisco
Wijnand J. C. Velden: Beckman Research Institute of the City of Hope
Ichie Ojiro: Duke University
Ikumi Takayama: Duke University
Bryan Faust: University of California, San Francisco
Linus Li: University of California, San Francisco
Nagarajan Vaidehi: Beckman Research Institute of the City of Hope
Aashish Manglik: University of California, San Francisco
Hiroaki Matsunami: Duke University

Nature, 2024, vol. 635, issue 8038, 499-508

Abstract: Abstract 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)1. 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 odorants2. 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 strategy3. 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.

Date: 2024
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DOI: 10.1038/s41586-024-08126-0

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