Structural basis of odorant recognition by a human odorant receptor

Billesboelle, Christian; March, Claire A. de; Velden, Wijnand J C van der; Ma, Ning; Tewari, Jeevan; Torrent, Claudia Llinás del; Li, Linus; Faust, Bryan; Vaidehi, Nagarajan; Matsunami, Hiroaki; Manglik, Aashish

doi:10.1101/2022.12.20.520951

Cited by 17 publications

(43 citation statements)

References 74 publications

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“…The ECL2 predicted by AF2 seems unique and was found to be rather stable in MD simulations. The correctness of the AF2 ECL2 folding was recently confirmed by the CryoEM structure of OR51E2 . However, we found a binding site occlusion that compromises the applicability of the AF2 model for structure-based investigations, as observed also in other studies. ,, …”

Section: Discussionsupporting

confidence: 72%

“…Instead, AF2 differs from GPCR ECL2 folds and groups in a separate region of the ECL2 space (Figure , black dots). Interestingly, the CryoEM structure of the odorant receptor OR51E2 was recently solved and described in a preprint article . For this structure, the ECL2 folding looks highly similar to that predicted by AlphaFold.…”

Section: Results and Discussionmentioning

confidence: 73%

“…In Figure 5 , it is possible to appreciate the difference in the shift of TM7 residues in the two models: position 7.42 is represented by F278 in the model from AF2 but by T279 in the model from HM. Only when OR experimental structures are released, 138 will it be possible to assess which binding site models better capture the structural features of OR5K1. However, our work demonstrates that it is possible to build predictive structural models despite their quality.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the CryoEM structure of the odorant receptor OR51E2 was recently solved and described in a preprint article. 74 For this structure, the ECL2 folding looks highly similar to that predicted by AlphaFold.…”

Section: ■ Introductionmentioning

confidence: 89%

“…The correctness of the AF2 ECL2 folding was recently confirmed by the CryoEM structure of OR51E2. 74 However, we found a binding site occlusion that compromises the applicability of the AF2 model for structurebased investigations, as observed also in other studies. 68,80,96 We found that the optimization of the binding site was a necessary step for both HM and AF2 models.…”

Section: ■ Conclusionmentioning

confidence: 98%

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Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1

Nicoli

Haag

Marcinek

et al. 2023

J. Chem. Inf. Model.

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With approximately 400 encoding genes in humans, odorant receptors (ORs) are the largest subfamily of class A G protein-coupled receptors (GPCRs). Despite its high relevance and representation, the odorant-GPCRome is structurally poorly characterized: no experimental structures are available, and the low sequence identity of ORs to experimentally solved GPCRs is a significant challenge for their modeling. Moreover, the receptive range of most ORs is unknown. The odorant receptor OR5K1 was recently and comprehensively characterized in terms of cognate agonists. Here, we report two additional agonists and functional data of the most potent compound on two mutants, L104 3.32 and L255 6.51 . Experimental data was used to guide the investigation of the binding modes of OR5K1 ligands into the orthosteric binding site using structural information from AI-driven modeling, as recently released in the AlphaFold Protein Structure Database, and from homology modeling. Induced-fit docking simulations were used to sample the binding site conformational space for ensemble docking. Mutagenesis data guided side chain residue sampling and model selection. We obtained models that could better rationalize the different activity of active (agonist) versus inactive molecules with respect to starting models and also capture differences in activity related to minor structural differences. Therefore, we provide a model refinement protocol that can be applied to model the orthosteric binding site of ORs as well as that of GPCRs with low sequence identity to available templates.

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Section: Discussionsupporting

confidence: 72%

Section: Results and Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 89%

Section: ■ Conclusionmentioning

confidence: 98%

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Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1

Nicoli

Haag

Marcinek

et al. 2023

J. Chem. Inf. Model.

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The complexities of ligand/receptor interactions: Exploring the role of molecular vibrations and quantum tunnelling

Pagán

2024

BioEssays

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Molecular vibrations and quantum tunneling may link ligand binding to the function of pharmacological receptors. The well‐established lock‐and‐key model explains a ligand's binding and recognition by a receptor; however, a general mechanism by which receptors translate binding into activation, inactivation, or modulation remains elusive. The Vibration Theory of Olfaction was proposed in the 1930s to explain this subset of receptor‐mediated phenomena by correlating odorant molecular vibrations to smell, but a mechanism was lacking. In the 1990s, inelastic electron tunneling was proposed as a plausible mechanism for translating molecular vibration to odorant physiology. More recently, studies of ligands’ vibrational spectra and the use of deuterated ligand analogs have provided helpful information to study this admittedly controversial hypothesis in metabotropic receptors other than olfactory receptors. In the present work, based in part on published experiments from our laboratory using planarians as an experimental organism, I will present a rationale and possible experimental approach for extending this idea to ligand‐gated ion channels.

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Molecular mechanisms of differentiation and class choice of olfactory sensory neurons

Hirota

2024

Genesis

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SummaryThe sense of smell is intricately linked to essential animal behaviors necessary for individual survival and species preservation. During vertebrate evolution, odorant receptors (ORs), responsible for detecting odor molecules, have evolved to adapt to changing environments, transitioning from aquatic to terrestrial habitats and accommodating increasing complex chemical environments. These evolutionary pressures have given rise to the largest gene family in vertebrate genomes. Vertebrate ORs are phylogenetically divided into two major classes; class I and class II. Class I OR genes, initially identified in fish and frog, have persisted across vertebrate species. On the other hand, class II OR genes are unique to terrestrial animals, accounting for ~90% of mammalian OR genes. In mice, each olfactory sensory neuron (OSN) expresses a single functional allele of a single OR gene from either the class I or class II OR repertoire. This one neuron‐one receptor rule is established through two sequential steps: specification of OR class and subsequent exclusive OR expression from the corresponding OR class. Consequently, OSNs acquire diverse neuronal identities during the process of OSN differentiation, enabling animals to detect a wide array of odor molecules. This review provides an overview of the OSN differentiation process through which OSN diversity is achieved, primarily using the mouse as a model animal.

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Structural basis of odorant recognition by a human odorant receptor

Cited by 17 publications

References 74 publications

Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1

Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1

The complexities of ligand/receptor interactions: Exploring the role of molecular vibrations and quantum tunnelling

Molecular mechanisms of differentiation and class choice of olfactory sensory neurons

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