scholarly journals The structural basis of odorant recognition in insect olfactory receptors

Nature ◽  
2021 ◽  
Author(s):  
Josefina del Mármol ◽  
Mackenzie A. Yedlin ◽  
Vanessa Ruta
Keyword(s):  
Olfactory Receptor ◽  
Hydrophobic Interactions ◽  
Olfactory Receptors ◽  
Binding Pocket ◽  
Structural Basis ◽  
Structural Determinants ◽  
Cryo Electron Microscopy ◽  
Common Strategy ◽  
Olfactory Systems ◽  
Discriminatory Capacity

AbstractOlfactory systems must detect and discriminate amongst an enormous variety of odorants1. To contend with this challenge, diverse species have converged on a common strategy in which odorant identity is encoded through the combinatorial activation of large families of olfactory receptors1–3, thus allowing a finite number of receptors to detect a vast chemical world. Here we offer structural and mechanistic insight into how an individual olfactory receptor can flexibly recognize diverse odorants. We show that the olfactory receptor MhOR5 from the jumping bristletail4Machilis hrabei assembles as a homotetrameric odorant-gated ion channel with broad chemical tuning. Using cryo-electron microscopy, we elucidated the structure of MhOR5 in multiple gating states, alone and in complex with two of its agonists—the odorant eugenol and the insect repellent DEET. Both ligands are recognized through distributed hydrophobic interactions within the same geometrically simple binding pocket located in the transmembrane region of each subunit, suggesting a structural logic for the promiscuous chemical sensitivity of this receptor. Mutation of individual residues lining the binding pocket predictably altered the sensitivity of MhOR5 to eugenol and DEET and broadly reconfigured the receptor’s tuning. Together, our data support a model in which diverse odorants share the same structural determinants for binding, shedding light on the molecular recognition mechanisms that ultimately endow the olfactory system with its immense discriminatory capacity.

scholarly journals The structural basis of odorant recognition in insect olfactory receptors

2021 ◽  
Author(s):  
Josefina del Mármol ◽  
Mackenzie Yedlin ◽  
Vanessa Ruta
Keyword(s):  
Olfactory Receptors ◽  
Binding Pocket ◽  
Structural Basis ◽  
Structural Determinants ◽  
Functional Studies ◽  
Chemical Recognition ◽  
Common Strategy ◽  
Olfactory Systems ◽  
Mechanistic Basis ◽  
Insight Into

AbstractOlfactory systems must detect and discriminate an enormous diversity of chemicals in the environment. To contend with this challenge, diverse species have converged on a common strategy in which odorant identity is encoded through the combinatorial activation of large families of olfactory receptors (ORs), thus allowing a finite number of receptors to detect an almost infinite chemical world. Although most individual ORs are sensitive to a variety of odorants, the structural basis for such flexible chemical recognition remains unknown. Here, we combine cryo-electron microscopy with functional studies of receptor tuning to gain insight into the structural and mechanistic basis of promiscuous odorant recognition. We show that OR5 from the jumping bristletail, Machilis hrabei, assembles as a homo-tetrameric odorant-gated ion channel with broad chemical tuning. We elucidated the structure of OR5 in multiple gating states, alone and in complex with two of its agonists—the odorant eugenol and the insect repellent DEET. Both ligands bind to a common binding site located in the transmembrane region of each subunit, composed of a simple geometric arrangement of aromatic and hydrophobic residues. We reveal that binding is mediated by hydrophobic, non-directional interactions with residues distributed throughout the binding pocket, enabling the flexible recognition of structurally distinct odorants. Mutation of individual residues lining the binding pocket predictably altered OR5’s sensitivity to eugenol and DEET and broadly reconfigured the receptor’s tuning, supporting a model in which diverse odorants share the same structural determinants for binding. Together, these studies provide structural insight into odorant detection, shedding light onto the molecular recognition mechanisms that ultimately endow the olfactory system with its immense discriminatory capacity.

scholarly journals Structural basis for subtype-specific inhibition of the P2X7 receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Akira Karasawa ◽  
Toshimitsu Kawate
Keyword(s):  
P2x7 Receptor ◽  
Hydrophobic Interactions ◽  
Binding Pocket ◽  
Drug Binding ◽  
Structural Basis ◽  
Atp Binding ◽  
Allosteric Site ◽  
Channel Opening ◽  
A Site ◽  
Novel Drug

The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP-binding pocket in a groove formed between two neighboring subunits. This novel drug-binding pocket accommodates a diversity of small molecules mainly through hydrophobic interactions. Functional assays propose that these compounds allosterically prevent narrowing of the drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP-binding pocket. These novel mechanistic insights will facilitate the development of P2X7-specific drugs for treating human diseases.

scholarly journals Structural basis for VIPP1 oligomerization and maintenance of thylakoid membrane integrity

2020 ◽  
Author(s):  
Tilak Kumar Gupta ◽  
Sven Klumpe ◽  
Karin Gries ◽  
Steffen Heinz ◽  
Wojciech Wietrzynski ◽  
...  
Keyword(s):  
Membrane Integrity ◽  
Point Mutations ◽  
Binding Pocket ◽  
Thylakoid Membranes ◽  
Lipid Binding ◽  
Structural Basis ◽  
Amphipathic Helices ◽  
Cryo Electron Microscopy

AbstractVesicle-inducing protein in plastids (VIPP1) is essential for the biogenesis and maintenance of thylakoid membranes, which transform light into life. However, it is unknown how VIPP1 performs its vital membrane-shaping function. Here, we use cryo-electron microscopy to determine structures of cyanobacterial VIPP1 rings, revealing how VIPP1 monomers flex and interweave to form basket-like assemblies of different symmetries. Three VIPP1 monomers together coordinate a non-canonical nucleotide binding pocket that is required for VIPP1 oligomerization. Inside the ring’s lumen, amphipathic helices from each monomer align to form large hydrophobic columns, enabling VIPP1 to bind and curve membranes. In vivo point mutations in these hydrophobic surfaces cause extreme thylakoid swelling under high light, indicating an essential role of VIPP1 lipid binding in resisting stress-induced damage. Our study provides a structural basis for understanding how the oligomerization of VIPP1 drives the biogenesis of thylakoid membranes and protects these life-giving membranes from environmental stress.

scholarly journals Decoding the olfactory map: targeted transcriptomics link olfactory receptors to glomeruli

2021 ◽  
Author(s):  
Kevin Zhu ◽  
Shawn Burton ◽  
Maira Nagai ◽  
Justin Silverman ◽  
Claire De March ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
High Throughput ◽  
Olfactory Receptor ◽  
Specific Activity ◽  
Olfactory Receptors ◽  
Receptor Expression ◽  
Central Neurons ◽  
Target Capture ◽  
Olfactory Systems ◽  
Peripheral Sensory

Abstract Sensory processing in olfactory systems is organized across olfactory bulb glomeruli, wherein axons of peripheral sensory neurons expressing the same olfactory receptor co-terminate to transmit receptor-specific activity to central neurons. Understanding how receptors map to glomeruli is therefore critical to understanding olfaction. High-throughput spatial transcriptomics is a rapidly advancing field, but low-abundance olfactory receptor expression within glomeruli has previously precluded high-throughput mapping of receptors to glomeruli. Here we combined sequential sectioning along the anteroposterior, dorsoventral, and mediolateral axes with target capture enrichment sequencing to overcome low-abundance target expression. This strategy allowed us to spatially map 86% of olfactory receptors across the olfactory bulb and uncover a relationship between OR sequence and glomerular position.

scholarly journals Molecular and Structural Basis of Olfactory Sensory Neuron Coalescence by Kirrel Receptors

2021 ◽  
Author(s):  
Jing Wang ◽  
Neelima Vaddadi ◽  
Joseph S. Pak ◽  
Yeonwoo Park ◽  
Sabrina Quilez ◽  
...  
Keyword(s):  
Sensory Neuron ◽  
Hydrophobic Interactions ◽  
Structural Basis ◽  
Accessory Olfactory Bulb ◽  
Secondary Interaction ◽  
Dimerization Interface ◽  
Olfactory Systems ◽  
Necessary And Sufficient ◽  
The Brain

ABSTRACTProjections from sensory neurons of olfactory systems coalesce into glomeruli in the brain. The Kirrel receptors are believed to homodimerize via their ectodomains and help separate sensory neuron axons into Kirrel2- or Kirrel3-expressing glomeruli. Here we present the crystal structures of homodimeric Kirrel receptors and show that the closely related Kirrel2 and Kirrel3 have evolved specific sets of polar and hydrophobic interactions, respectively, disallowing heterodimerization while preserving homodimerization, likely resulting in proper segregation and coalescence of Kirrel-expressing axons into glomeruli. We show that the dimerization interface at the N-terminal IG domains is necessary and sufficient to create homodimers, and fail to find evidence for a secondary interaction site in Kirrel ectodomains. Furthermore, we show that abolishing dimerization of Kirrel3 in vivo leads to improper formation of glomeruli in the mouse accessory olfactory bulb as observed in Kirrel3-/- animals. Our results provide strong evidence for Kirrel3 homodimerization controlling axonal coalescence.

scholarly journals Molecular reconstruction of recurrent evolutionary switching in olfactory receptor specificity

2021 ◽  
Author(s):  
Lucia L. Prieto-Godino ◽  
Hayden R. Schmidt ◽  
Richard Benton
Keyword(s):  
Ligand Binding ◽  
Olfactory Receptor ◽  
Olfactory Receptors ◽  
Binding Pocket ◽  
Amino Acid Identity ◽  
Major Effect ◽  
Ligand Docking ◽  
Ionotropic Receptor ◽  
Ligand Binding Pocket ◽  
Receptor Interactions

AbstractOlfactory receptor repertoires exhibit remarkable functional diversity, but how these proteins have evolved is poorly understood. Through analysis of extant and ancestrally-reconstructed drosophilid olfactory receptors from the Ionotropic Receptor (IR) family, we investigated evolution of two organic acid-sensing receptors, IR75a and IR75b. Despite their low amino acid identity, we identify a common “hotspot” in their ligand-binding pocket that has a major effect on changing the specificity of both IRs, as well as at least two distinct functional transitions in IR75a during evolution. Ligand-docking into IR models predicts that the hotspot does not contact odor molecules, suggesting that this residue indirectly influences ligand/receptor interactions. Moreover, we show that odor specificity is refined by changes in additional, receptor-specific sites, including those outside the ligand-binding pocket. Our work reveals how a core, common determinant of ligand-tuning acts within epistatic and allosteric networks of substitutions to lead to functional evolution of olfactory receptors.

scholarly journals Olfactory receptors are sensitive to molecular volume of odorants

2015 ◽  
Author(s):  
Majid Saberi ◽  
Hamed Seyed-allaei
Keyword(s):  
Olfactory Receptor ◽  
Experimental Studies ◽  
Chemical Properties ◽  
Olfactory Receptors ◽  
Binding Pocket ◽  
Olfactory Receptor Neuron ◽  
Neural Response ◽  
Molecular Volume ◽  
Combinatorial Encoding ◽  
Two Parameters

To study olfaction,
 first we should know which physical or chemical properties of odorant molecules determine 
 the response of olfactory receptor neurons, 
 and then we should study the effect of those properties on the combinatorial encoding in olfactory system.
 
 In this work we show that the response of an olfactory receptor neuron in Drosophila depends on molecular volume of an odorant; 
 The molecular volume determines the upper limits of the neural response, 
 while the actual neural response may depend on other properties of the molecules.
 Each olfactory receptor prefers a particular volume, 
 with some degree of flexibility.
 These two parameters predict the volume and flexibility of the binding-pocket of the olfactory receptors, 
 which are the targets of structural biology studies. 
 
 At the end we argue that the molecular volume can affects the quality of perceived smell of an odorant via the combinatorial encoding,
 molecular volume may mask other underlying relations between properties of molecules and neural responses 
 and we suggest a way to improve the selection of odorants in further experimental studies.

scholarly journals Cryo-EM structure of the B cell co-receptor CD19 bound to the tetraspanin CD81

Science ◽  
2021 ◽  
Vol 371 (6526) ◽  
pp. 300-305
Author(s):  
Katherine J. Susa ◽  
Shaun Rawson ◽  
Andrew C. Kruse ◽  
Stephen C. Blacklow
Keyword(s):  
B Cell ◽  
Rational Design ◽  
Cell Receptor ◽  
Binding Pocket ◽  
Structural Basis ◽  
Transmembrane Helices ◽  
Critical Determinant ◽  
Cell Dysfunction ◽  
Cryo Electron Microscopy ◽  
Binding Surface

Signaling through the CD19-CD81 co-receptor complex, in combination with the B cell receptor, is a critical determinant of B cell development and activation. It is unknown how CD81 engages CD19 to enable co-receptor function. Here, we report a 3.8-angstrom structure of the CD19-CD81 complex bound to a therapeutic antigen-binding fragment, determined by cryo–electron microscopy (cryo-EM). The structure includes both the extracellular domains and the transmembrane helices of the complex, revealing a contact interface between the ectodomains that drives complex formation. Upon binding to CD19, CD81 opens its ectodomain to expose a hydrophobic CD19-binding surface and reorganizes its transmembrane helices to occlude a cholesterol binding pocket present in the apoprotein. Our data reveal the structural basis for CD19-CD81 complex assembly, providing a foundation for rational design of therapies for B cell dysfunction.

scholarly journals Molecular reconstruction of recurrent evolutionary switching in olfactory receptor specificity

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Lucia L Prieto-Godino ◽  
Hayden R Schmidt ◽  
Richard Benton
Keyword(s):  
Ligand Binding ◽  
Olfactory Receptor ◽  
Olfactory Receptors ◽  
Binding Pocket ◽  
Amino Acid Identity ◽  
Major Effect ◽  
Receptor Specificity ◽  
Ionotropic Receptor ◽  
Ligand Binding Pocket ◽  
Acid Identity

Olfactory receptor repertoires exhibit remarkable functional diversity, but how these proteins have evolved is poorly understood. Through analysis of extant and ancestrally-reconstructed drosophilid olfactory receptors from the Ionotropic receptor (Ir) family, we investigated evolution of two organic acid-sensing receptors, Ir75a and Ir75b. Despite their low amino acid identity, we identify a common 'hotspot' in their ligand-binding pocket that has a major effect on changing the specificity of both Irs, as well as at least two distinct functional transitions in Ir75a during evolution. Moreover, we show that odor specificity is refined by changes in additional, receptor-specific sites, including those outside the ligand-binding pocket. Our work reveals how a core, common determinant of ligand-tuning acts within epistatic and allosteric networks of substitutions to lead to functional evolution of olfactory receptors.

scholarly journals Different conformational responses of the β2-adrenergic receptor-Gs complex upon binding of the partial agonist salbutamol or the full agonist isoprenaline

2020 ◽  
Author(s):  
Fan Yang ◽  
Shenglong Ling ◽  
Yingxin Zhou ◽  
Yanan Zhang ◽  
Pei Lv ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Hydrophobic Interactions ◽  
Partial Agonist ◽  
Binding Pocket ◽  
Structural Basis ◽  
Spectroscopic Techniques ◽  
Toggle Switch ◽  
Intracellular Loop ◽  
Full Agonist ◽  
Β2 Adrenergic Receptor

Abstract GPCRs are responsible for most cytoplasmic signaling in response to extracellular ligands with different efficacy profiles. Various spectroscopic techniques have identified that agonists exhibiting varying efficacies can selectively stabilize a specific conformation of the receptor. However, the structural basis for activation of the GPCR-G protein complex by ligands with different efficacies is incompletely understood. To better understand the structural basis underlying the mechanisms by which ligands with varying efficacies differentially regulate the conformations of receptors and G proteins, we determined the structures of β2AR-Gαs$\beta $γ bound with partial agonist salbutamol or bound with full agonist isoprenaline using single-particle cryo-electron microscopy at resolutions of 3.26 Å and 3.80 Å, respectively. Structural comparisons between the β2AR-Gs-salbutamol and β2AR-Gs-isoprenaline complexes demonstrated that the decreased binding affinity and efficacy of salbutamol compared with those of isoprenaline might be attributed to the weakened hydrogen bonding interactions, attenuated hydrophobic interactions in the orthosteric binding pocket and different conformational changes in the rotamer toggle switch in TM6. Moreover, the observed stronger interactions between the intracellular loop 2 or 3 (ICL2 or ICL3) of β2AR and Gαs with the binding of salbutamol versus isoprenaline might decrease phosphorylation in the salbutamol-activated β2AR-Gs complex. From the observed structural differences between these complexes of β2AR, a mechanism of β2AR activation by partial and full agonists is proposed to shed structural insights for β2AR desensitization.

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