Presentation Details
| Multistep Ligand Association Reveals How Dynamic Extracellular Gating Controls Odorant Agonism and Antagonism in Olfactory Receptors Mona A.Marie1, Ning Ma2, Da Takase4, Hiroaki Matsunami1, 3. 1Molecular Genetics and Microbiology Department, Duke Unversity School of Medicine, Durham, NC, USA.2Department of Computational & Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, NC, USA.3Department of Neurobiology, Duke University, Durham, NC, USA.4Sensory Science Research, Kao Corporation, Tochigi, Japan |
Abstract
Olfactory receptors (ORs) are class A GPCRs with broad ligand sensitivity, yet the mechanisms governing odorant selectivity and antagonism remain unclear. Using long-timescale ligand-association molecular dynamics simulations combined with Markov state models, Bayesian network analysis, and cell-based assays, we resolve distinct association and intermediate states during ligand entry across OR classes. In the class I receptor OR51E2, propionate (C3) enters via two extracellular routes and first populates a gate-associated intermediate state; productive association requires opening and re-closure of an ECL2–ECL3 gate. Simulations predicted that heptanoate (C7) preferentially stabilizes the same intermediate gate-associated state, reducing the probability of C3 reaching the associated state; competition assays explain our previous C7 antagonism observations. In the class II receptor OR1A1, hydrophobic ligands associate predominantly through membrane-facing transmembrane pathways. These findings identify ligand-entry intermediates, state-transition probabilities, and gate dynamics as key determinants of OR selectivity and antagonism.
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.
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.
Content Locked. Log into a registered attendee account to access this presentation.