Presentation Details
| Structural Exploration of Musk Recognition and Activation Mechanisms of Odorant Receptors Dan Takase, Hiroaki Matsunami. Duke University, Durham, NC, USA |
Abstract
Odorant receptors (ORs) constitute the largest gene superfamily in vertebrates, enabling the detection of a wide variety of odorants. Recent advances in cryo-electron microscopy have facilitated the structural determination of membrane proteins. However, it is still difficult to solve the OR structures due to their inherent instability and typically low cell-surface expression in a heterologous cell system. As a result, only a few OR structures have been reported to date. The limited structural information hampers our understanding of how ORs recognize various odorants and become activated upon ligand binding. To address this fundamental issue, we took advantage of AlphaFold 3 (AF3), a cutting-edge prediction tool for protein structures and interactions with biomolecules. Validation of AF3 models for ORs allowed us to explore ligand recognition logic of a specific OR and common activation mechanisms of OR family. Regarding ligand recognition, we are focusing on OR5A2, a Class II OR that can recognize multiple classes of musk odorants, and tackling how OR5A2 achieves high specificity while simultaneously accommodating the structurally diverse musk compounds. Site-directed mutagenesis guided by the AF3 binding poses identified critical residues for musk recognition. For the activation mechanism, we compared contact scores of each residue pair between active- and inactive-like AF3 models. This analysis suggests that while the OR family may share the same activation features with non-olfactory Class A GPCRs, it also possesses a unique set of activation residue pairs that reflect OR-specific sequence conservation. This study will provide valuable insights into the molecular mechanisms of odor perception.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
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