Crucial role of copper in detection of metal-coordinating odorants

Duan, Xu-Fang; Block, Eric; Li, Zhen; Connelly, Timothy; Zhang, Jian; Huang, Zhimin; Su, Xubo; Pan, Yixin; Wu, Lifang; Chi, Qiuyi; Thomas, Siji; Zhang, Shaozhong; Ma, Minghong; Matsunami, Hiroaki; Chen, Guoqiang; Zhuang, Huisheng

doi:10.1073/pnas.1111297109

Cited by 107 publications

(107 citation statements)

References 42 publications

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“…As the electron traverses the active site, it may undertake several paths: (i) elastic tunneling, where no energy is lost or gained by the electron; (ii) inelastic tunneling (IET), where the electron may donate or accept a quantum of energy during transfer; and (iii) subsequently higher ordered inelastic processes (61)(62)(63). The hypothesized presence of a possible metal cofactor site-acting to assist either in binding or in a later activation step-at ORs, GPCRs, and non-GPCR chemokine receptors is supported by altered behavioral response (64)(65)(66), physiological response (66)(67)(68), theory (69,70), and in vitro observations (70)(71)(72)(73)(74)(75)(76)(77)(78)(79). 3.…”

Section: Theoretical Predictionsmentioning

confidence: 99%

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

Hoehn

Nichols

McCorvy

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Recently, an alternative theory concerning the method by which olfactory proteins are activated has garnered attention. This theory proposes that the activation of olfactory G protein-coupled receptors occurs by an inelastic electron tunneling mechanism that is mediated through the presence of an agonist with an appropriate vibrational state to accept the inelastic portion of the tunneling electron's energy. In a recent series of papers, some suggestive theoretical evidence has been offered that this theory may be applied to nonolfactory G protein- O lfaction-and other chemo-sensitive sensory processes-is an important information-gathering technique for organisms of many clades and kingdoms. Specifically, human olfaction is known to occur by activation of olfactory receptors (ORs)-a subclass of G protein-coupled receptors (GPCRs)-located within the nasal epithelium and mediating responses within the olfactory bulb, where it is encoded and conveys information to the amygdala, the orbitofrontal cortex, and the hippocampus (1, 2). The discovery and the cloning of ORs led to the joint 2004 Nobel Prize in Physiology and Medicine to Richard Axel and Linda Buck. (3) GPCRs are 7-helical transmembrane proteins, facilitating communication from extracellular ligand signals to the cellular interior through activation of (interior) G proteins, while maintaining the integrity of the membrane (4). GPCRs are activated by an appropriate agonist moving into the protein's orthosteric binding site, resulting in a conformational change within the helical bundle. This structural change leads to altered conformations of the intracellular loops that couple to appropriate signaling molecules within the cell, e.g., G proteins. A recent series of papers has experimentally determined activated/inactivated states through isotopic-tagged receptors with NMR spectroscopy (5-7). An additional work used molecular dynamics to provide structural insights into how the agonist may assist the interchange between conformations through several proposed peptide sidechain pathways by examining the structures of the activated and inactivated µ-opioid receptor (8). Additionally, photon-induced conformational changes in lightsensitive proteins have also been observed (9, 10).Recently, an iteration of the vibrational theory of olfaction (VTO)-suggested and advocated by Luca Turin (11, 12)-has arisen and has gained both supporters (13-16) and detractors (17, 18); the novelty of this incarnation of the VTO is ascribable to its nonthermal-and nonphoton-based mechanism. Turin's theory is a contemporary reincarnation of the more classical theory proposed by Dyson (19), Wright (20), and Wright and Serenius (21), where the activation of the olfactory receptor is performed-or sensitive to-the molecular vibrations of the olfactant. Dyson suggested that the molecular vibrations of the agonist were exactly responsible for the activation of the protein. These vibrations were entirely thermally excited, as no mechanism for photoexcitation is available within the body. Th...

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Section: Theoretical Predictionsmentioning

confidence: 99%

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

Hoehn

Nichols

McCorvy

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…ORs belong to the superfamily of class A G protein-coupled receptors (GPCRs), which are known to be activated through allosteric conformational changes induced upon ligand binding even without triggering any kind of electron transfer processes. Ligand-receptor interactions can be both attractive and repulsive, involving hydrogen bonding, van der Waals, cation-π, π-π, ion-ion, dipoledipole, steric, and hydrophobic interactions with the receptor, with water channels and bridging water molecules mediating hydrogen bonds, as well as metal-ion coordination, as we have recently demonstrated in the latter case (15,16). Therefore, molecular shape can be considered a "straw-man" alternative to the vibration theory when describing the differing affinities of ligands bound to GPCRs (17,18), including isotopomers (19,20).…”

Section: Significancementioning

confidence: 99%

“…In addition, we present related studies on the response of various human and mouse ORs to other deuterated and nondeuterated odorants, including (methylthio)-methanethiol (MTMT, 8; Fig. 1C) and bis(methylthiomethyl) disulfide (9), studied in connection with our investigation of the role of copper coordination in the recognition of both sulfur-containing odorants by the mouse (methylthio)methanethiol receptor, MOR244-3 (15,16). Insofar as the ability to distinguish odors of isotopomers directly tests the predictions of the vibration theory, the comparative response of human and mouse ORs to isotopomers of these selected ligands in the heterologous OR expression system constitutes a robust test of the vibration theory.…”

Section: Significancementioning

confidence: 99%

“…Our assay included MTMT (8) and MTMTd 5 (8-d 5 ) (Fig. 1C), as well as bis(methylthiomethyl) disulfide (9) and 9-d 10 , ligands for mouse receptor MOR244-3, which are notable for requiring copper for ligand binding and whose active site we have modeled (15,16). Deuterated compound (8-d 5 ) was prepared in several steps from dimethyl sulfoxide-d 6 and then oxidized to 9-d 10 ; these compounds had ∼100% d 5 and d 10 deuterium incorporation, respectively, according to GC-MS.…”

Section: Response Of a Human Musk Or To Deuterated And Nondeuteratedmentioning

confidence: 99%

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Implausibility of the vibrational theory of olfaction

Block

Jang

Matsunami

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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115

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The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/ deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse ORs, responded similarly to normal, deuterated, and 13 C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d 30 lacks the 1,380-to 1,550-cm −1 IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. These and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory.olfaction | isotopomers | cyclopentadecanone | muscone | electron transfer I n 1870, the British physician William Ogle wrote: "As in the eye and the ear the sensory impression is known to result not from the contact of material particles given off by the object seen or heard, but from waves or undulations of the ether or the air, one cannot but suspect that the same may be true in the remaining sense, and that the undulatory theory of smell. . . [may be] the true one" (1, 2). Of the 29 different "theories of odour" listed in the 1967 edition of The Chemical Senses (3), nine associate odor with vibrations, particularly those theories championed by Dyson (4, 5) and Wright (6-8). However, the premise that olfaction involves detection of vibrational frequencies of odorants remains highly speculative because neither the structures of the odorant receptors (ORs) nor the binding sites or the activation mechanisms triggered upon odorant binding to ORs have been established. In 1996-1997, Turin (9-12) elaborated on the undulatory theory of smell, as considered in more detail below, and suggested that a mechanism analogous to inelastic electron tunneling spectroscopy (13) may be involved, where tunneling electrons in the receptor probe the vibrational frequencies of odorants. In 2013, Gane et al. (14) In judging the plausibility...

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“…9,35,36 The effects were related to the states, valences and sizes of metals. For example, copper ions could react with specific odorants to enhance the responses of MOR244-3, 37 while copper nanoparticles could not improve the olfactory sensing. 21 In this study, the improvement of odorant detection sensitivity of the olfactory cell-based biosensor was realized by combining NanoZn with olfactory cells.…”

Section: Discussionmentioning

confidence: 99%

Zinc Nanoparticles-equipped Bioelectronic Nose Using a Microelectrode Array for Odorant Detection

Zhang

et al. 2016

ANAL. SCI.

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Bioelectronic noses, such as olfactory cell-and receptor-based biosensors, have important applications for biomimetic odorant detection in various fields. Here, a nanoparticle-equipped biosensor was designed to record extracellular potentials from olfactory receptor cells effectively. In this research, a microelectrode array (MEA) was combined with olfactory epitheliums as the olfactory biosensor to record electrophysiological signals of receptor cells in the epitheliums. Zinc nanoparticles (NanoZn) were employed along with the biosensor for different kinds of odorant measurements, which improved the electrophysiological responses to odor molecules. The NanoZn-equipped biosensor showed greater performance, such as a higher sensitivity and a larger signal-to-noise ratio, than that without the nanoparticles. Thus, this approach provided a promising method to improve the detecting performance of biosensors based on olfactory cells and receptors, which would bring broad application prospects for bioelectronic noses in environmental monitoring, food analysis, and healthcare diagnosis.

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Crucial role of copper in detection of metal-coordinating odorants

Cited by 107 publications

References 42 publications

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

Implausibility of the vibrational theory of olfaction

Zinc Nanoparticles-equipped Bioelectronic Nose Using a Microelectrode Array for Odorant Detection

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