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Journal Article•DOI•

α-Conotoxin Vc1.1 Structure-Activity Relationship at the Human α9α10 Nicotinic Acetylcholine Receptor Investigated by Minimal Side Chain Replacement.

Xin Chu1, Han-Shen Tae2, Qingliang Xu1, Tao Jiang1, David J. Adams2, Rilei Yu1 •
Chinese Ministry of Education1, Illawarra Health & Medical Research Institute2
16 Oct 2019-ACS Chemical Neuroscience (ACS Chem Neurosci)-Vol. 10, Iss: 10, pp 4328-4336
TL;DR: The results suggest that the hydroxyl group of Vc1.1 Y10 forms hydrogen bond with the carbonyl group of α9 N107 and a hydrogen bond donor is required, whereas Vc2.1 S4 is adjacent to the α9 D166 and D169, and a positive charge residue at this position increases the binding affinity of V c1.
Abstract: α-Conotoxin Vc1.1 inhibits the nicotinic acetylcholine receptor (nAChR) α9α10 subtype and has the potential to treat neuropathic chronic pain. To date, the crystal structure of Vc1.1-bound α9α10 nAChR remains unavailable; thus, understanding the structure-activity relationship of Vc1.1 with the α9α10 nAChR remains challenging. In this study, the Vc1.1 side chains were minimally modified to avoid introducing large local conformation perturbation to the interactions between Vc1.1 and α9α10 nAChR. The results suggest that the hydroxyl group of Vc1.1, Y10, forms a hydrogen bond with the carbonyl group of α9 N107 and a hydrogen bond donor is required. However, Vc1.1 S4 is adjacent to the α9 D166 and D169, and a positive charge residue at this position increases the binding affinity of Vc1.1. Furthermore, the carboxyl group of Vc1.1, D11, forms two hydrogen bonds with α9 N154 and R81, respectively, whereas introducing an extra carboxyl group at this position significantly decreases the potency of Vc1.1. Second-generation mutants of Vc1.1 [S4 Dab, N9A] and [S4 Dab, N9W] increased potency at the α9α10 nAChR by 20-fold compared with that of Vc1.1. The [S4 Dab, N9W] mutational effects at positions 4 and 9 of Vc1.1 are not cumulative but are coupled with each other. Overall, our findings provide valuable insights into the structure-activity relationship of Vc1.1 with the α9α10 nAChR and will contribute to further development of more potent and specific Vc1.1 analogues.

Summary (1 min read)

Jump to: [1. Introduction] – [2. Results and discussion] and [3. Conclusions]

1. Introduction

  • Conotoxins are disulfide-rich peptides from the venom of marine snails of the Conus genus.
  • In the nervous system, they mediate the role of the neurotransmitter acetylcholine and are involved in rapid synaptic transmission.
  • 25-27 The evidence that the nAChRs play a role in a number of different neuronal functions and disorders has given impetus to the search for drugs that selectively modulate different nAChR subtypes.
  • 33,34 To date, the crystal structure of Vc1.1 bound-α9α10 nAChR remains unavailable, and computational modeling in combination with mutagenesis studies have been used as an effective method for understanding the structure-activity relationship.

2. Results and discussion

  • Specific Vc1.1 side chains were minimally modified to validate the previously determined binding modes of Vc1.1 and to understand the structure-activity relationship of Vc1.1 with the α9α10 nAChR.
  • The results disagree with their modeling studies in which two hydrogen bonds were identified between the hydroxyl group of Vc1.1 Y10 and the backbone H atom of α9 D119 and O atom of α9 N107 .
  • The K, Dab and Dap residues all possess a positively charged amine group at the side chain terminus, whereas their potency is remarkably different suggesting that appropriate length of the side chain is essential for the formation of favourable electrostatic interaction with the proposed D169 and D166 in their model .
  • The mutational effects of the [S4K, N9A] double mutation were not cumulative of the single mutations, since the double mutant could only select either the orientation of [S4K]Vc1.1 or [N9A]Vc1.1 upon binding to the receptor.
  • The second generation [S4Dab, N9A]Vc1.1 and [S4Dab, N9W]Vc1.1 analogues were chemically synthesized, and their activity was determined at heterologously expressed hα9α10 nAChR.

3. Conclusions

  • In summary, using previously built α9α10 nAChR model as guidance, the authors designed a library of Vc1.1 analogues by introducing residues with similar physicochemical properties to the wild-type residues in order to validate the accuracy of the model and investigated the structure-activity relationship of Vc1.1 with the hα9α10 nAChR at the atomic level.
  • The authors findings suggest that Vc1.1 S4 forms hydrogen bonds with α9 D166 and D169, and introducing positively charged residues at this position can improve the potency.
  • The P6 is nearby D119, and the introduced Hyp6 approaches D119 and forms a hydrogen bond.
  • The side chain length and the number of negative charges are essential for residue at 10 position of Vc1.1.

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1
α-Conotoxin Vc1.1 Structure-Activity Relationship at the Human α9α10
Nicotinic Acetylcholine Receptor Investigated by Minimal Side Chain
Replacement
Xin Chu,
1,2ǂ
Han-Shen Tae,
3ǂ*
Qingliang Xu,
1,2
Tao Jiang,
1,2
David J. Adams,
3
and Rilei Yu
1,2,4*
1
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of
Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao
266003, China
2
Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for
Marine Science and Technology, Qingdao 266003, China
3
Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong,
Wollongong, New South Wales 2522, Australia
4
Innovation Center for Marine Drug Screening & Evaluation, Qingdao National
Laboratory for Marine Science and Technology, Qingdao 266003, China
*
Corresponding authors: hstae@uow.edu.au or ryu@ouc.edu.cn
ǂ
Both authors contributed equally to this manuscript.
2
ABSTRACT
α-Conotoxin Vc1.1 inhibits the nicotinic acetylcholine receptor (nAChR) α9α10
subtype and has the potential to treat neuropathic chronic pain. To date, the crystal
structure of Vc1.1 bound-α9α10 nAChR remains unavailable, thus understanding the
structure-activity relationship of Vc1.1 with the α9α10 nAChR remains challenging.
In this study, the Vc1.1 side chains were minimally modified to avoid introducing
large local conformation perturbation to the interactions between Vc1.1 and α9α10
nAChR. The results suggest that the hydroxyl group of Vc1.1, Y10, forms a hydrogen
bond with the carbonyl group of α9 N107 and a hydrogen bond donor is required,
whereas Vc1.1 S4 is adjacent to the α9 D166 and D169, and a positive charge residue
at this position increases the binding affinity of Vc1.1. Furthermore, the carboxyl
group of Vc1.1, D11, forms two hydrogen bonds with α9 N154 and R81 respectively,
whereas introducing an extra carboxyl group at this position significantly decreases
the potency of Vc1.1. Second generation mutants of Vc1.1 [S4Dab, N9A] and [S4Dab,
N9W] increased potency at the α9α10 nAChR by 20-fold compared with that of
Vc1.1. The [S4Dab, N9W] mutational effects at positions 4 and 9 of Vc1.1 are not
cumulative but are coupled with each other. Overall, our findings provide valuable
insights into the structure-activity relationship of Vc1.1 with the α9α10 nAChR and
will contribute to further development of more potent and specific Vc1.1 analogues.
KEYWORDS: α-Conotoxin, nicotinic acetylcholine receptor; structure-activity
relationship; unnatural amino acids; molecular dynamics simulations; mutagenesis
3
1. Introduction
Conotoxins are disulfide-rich peptides from the venom of marine snails of the
Conus genus.
1-3
The conopeptides range from 10 to 40 amino acids in length and have
a compact structure stabilized by several disulfide bonds.
4
Compared with other
natural peptide toxins, conotoxins have considerable advantages such as relatively
small molecular mass, structural stability, high selectivity, potency, and easy
synthesis.
5-9
α-Conotoxins were one of the earliest discovered conotoxins, usually composed
of 12 to 30 amino acid residues,
10
and can specifically target nicotinic acetylcholine
receptors (nAChRs).
11
Several α-conotoxins have shown promising therapeutic
potential
12
with a most prominent example being α-conotoxin Vc1.1 (Figure 1A).
13
Vc1.1 is a 16 amino acid, disulfide-bonded peptide identified from the venom of C.
victoria
14
and potently inhibits the α9α10 nAChR.
15-17
nAChRs are pentameric ligand-gated ion channels consisting of an extracellular
domain, a transmembrane domain and an intracellular domain and are expressed in
the central and peripheral nervous systems and non-neuronal cells.
18,19
The conotoxin
binding site is located at the extracellular domain contributed by the principal (+) and
complementary (−) components of two adjacent subunits (α1-α10, β1-β4, γ, δ or ε).
20
In the nervous system, they mediate the role of the neurotransmitter acetylcholine and
are involved in rapid synaptic transmission.
21-23
The non-neuronal functions of
nAChRs include cellular proliferation and regulation of the immune system. There are
many different nAChR subtypes with preferential distribution in the nervous system,
Citations
More filters
Journal Article•DOI•
Medicinal chemistry, pharmacology, and therapeutic potential of α-conotoxins antagonizing the α9α10 nicotinic acetylcholine receptor.

[...]

Xiao Li1, Han-Shen Tae2, Yanyan Chu1, Tao Jiang1, David J. Adams2, Rilei Yu1 •
Chinese Ministry of Education1, Illawarra Health & Medical Research Institute2
01 Jun 2021-Pharmacology & Therapeutics
TL;DR: The structure and function of the α9α10 nAChR are highlighted and studies of α-conotoxins targeting it are reviewed, including their three-dimensional structures, structure optimization strategies, and binding modes at the α 9α10nA chR, as well as their therapeutic potential.

22 citations

Journal Article•DOI•
α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia

[...]

Adam C. Kennedy1, Alessia Belgi1, Benjamin W. Husselbee1, David Spanswick2, David Spanswick3, David Spanswick4, Raymond S. Norton5, Andrea J. Robinson1 •
Monash University, Clayton campus1, Coventry Health Care2, University of Warwick3, Discovery Institute4, Monash University5
06 Aug 2020-Toxins
TL;DR: This review scrutinises the N-terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca2+ channels.
Abstract: Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets-nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABAB) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the N-terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca2+ channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions.

20 citations

Journal Article•DOI•
Mechanism of Action and Structure-Activity Relationship of α-Conotoxin Mr1.1 at the Human α9α10 Nicotinic Acetylcholine Receptor.

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Jiazhen Liang, Han-Shen Tae, Zitong Zhao, Xiao Li, Jinghui Zhang, Shen Chen, Tao Jiang, David H. Adams, Rilei Yu 
22 Sep 2022-Journal of Medicinal Chemistry
TL;DR: A formerly defined rat α7 nAChR targeting α-CTx Mr1.1 was chemically synthesized and displayed analgesic activity in the rat chronic constriction injury (CCI) pain model and therefore presents a promising drug candidate.
Abstract: α-Conotoxins (α-CTxs) can selectively target nicotinic acetylcholine receptors (nAChRs) and are important drug leads for the treatment of cancer, chronic pain, and neuralgia. Here, we chemically synthesized a formerly defined rat α7 nAChR targeting α-CTx Mr1.1 and evaluated its activity at human nAChRs. Mr1.1 was most potent at the human (h) α9α10 nAChR with a half-maximal inhibitory concentration (IC50) of 92.0 nM. Molecular dynamic simulations suggested that Mr1.1 favorably binds at the α10(+)α9(-) and α9(+)α9(-) sites via hydrogen bonds and salt bridges, stabilizing the channel in a closed conformation. Although Mr1.1 and another antagonist, α-CTx Vc1.1 share high sequence similarity and disulfide-bond framework, Mr1.1 has distinct orientations at hα9α10. Based on the Mr1.1-hα9α10 model, analogues were generated, and the more potent Mr1.1[S4Dap], antagonized hα9α10 with an IC50 of 4.0 nM. Furthermore, Mr1.1[S4Dap] displayed analgesic activity in the rat chronic constriction injury (CCI) pain model and therefore presents a promising drug candidate.

7 citations

Proceedings Article•DOI•
Alpha-family of Conotoxins: An Analysis of Structural Determinants

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Marineil C. Gomez1, Alisha Marcelle C. Aquino1, Andrea R. Matira1, Riggs Anton D. Alvarico1, Reincess E. Valbuena1, Lemmuel L. Tayo1 •
Mapúa Institute of Technology1
17 Oct 2019
TL;DR: The topological landscape of the conopeptides were influenced by the Cα backbone and the nature of the intervening amino acid, and are predominantly electron-poor regions, allowing them to act as Lewis acids, and may play a role in their ability to interact with ACh receptors.
Abstract: Conopeptides are small, disulfide-rich polypeptides that have great potential as sources of possible drug candidates due to their activity against membrane receptors and ion channels. A challenge to the faster high-throughput in silico screening of these potential drug candidates is their diversity in structure and relatively low sequence similarity despite similar functions. In this study, the conopeptides of the α-pharmacological family is studied based on their Cα backbone, surface topology and sequence analysis. Structural alignment using FATCAT shows good alignment of the conopeptides based on their RMSD values. The main factor contributing to the homology of their structures is not only the Cys (Cys) framework forming the disulfide bridges but also the number of intervening amino acids between the Cys residues and the length of the polypeptide. The topological landscape of the conopeptides were influenced by the Cα backbone and the nature of the intervening amino acid, and are predominantly electron-poor regions, allowing them to act as Lewis acids. This may play a role in their ability to interact with ACh receptors.

5 citations

Cites background from "α-Conotoxin Vc1.1 Structure-Activit..."

  • ...Indeed, a large number of subclassifications of receptors have been discovered using conopeptide probes [6], [10], [11], [12], [13]....

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Journal Article•DOI•
Marine Origin Ligands of Nicotinic Receptors: Low Molecular Compounds, Peptides and Proteins for Fundamental Research and Practical Applications

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Igor E. Kasheverov, Denis S. Kudryavtsev, Irina V. Shelukhina, G. M. Nikolaev, Yuri N. Utkin, Victor I. Tsetlin 
23 Jan 2022-Biomolecules
TL;DR: In this review, the purpose of the review is to briefly show what different compounds of marine origin, from low molecular weight ones to peptides and proteins, offer for understanding the structure and mechanism of action of nicotinic acetylcholine receptors (nAChRs) and for finding novel drugs to combat the diseases where nA ChRs may be involved.
Abstract: The purpose of our review is to briefly show what different compounds of marine origin, from low molecular weight ones to peptides and proteins, offer for understanding the structure and mechanism of action of nicotinic acetylcholine receptors (nAChRs) and for finding novel drugs to combat the diseases where nAChRs may be involved. The importance of the mentioned classes of ligands has changed with time; a protein from the marine snake venom was the first excellent tool to characterize the muscle-type nAChRs from the electric ray, while at present, muscle and α7 receptors are labeled with the radioactive or fluorescent derivatives prepared from α-bungarotoxin isolated from the many-banded krait. The most sophisticated instruments to distinguish muscle from neuronal nAChRs, and especially distinct subtypes within the latter, are α-conotoxins. Such information is crucial for fundamental studies on the nAChR revealing the properties of their orthosteric and allosteric binding sites and mechanisms of the channel opening and closure. Similar data are provided by low-molecular weight compounds of marine origin, but here the main purpose is drug design. In our review we tried to show what has been obtained in the last decade when the listed classes of compounds were used in the nAChR research, applying computer modeling, synthetic analogues and receptor mutants, X-ray and electron-microscopy analyses of complexes with the nAChRs, and their models which are acetylcholine-binding proteins and heterologously-expressed ligand-binding domains.

5 citations

References
More filters
Journal Article•DOI•
Chemical modification of conotoxins to improve stability and activity.

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David J. Craik1, David J. Adams1•
University of Queensland1
20 Jul 2007-ACS Chemical Biology
TL;DR: Manufactured interventions add to the array of post-translational modifications that occur naturally in conopeptides, enhancing the versatility of these peptides as tools in neuroscience and as drug leads.
Abstract: Conotoxins are small disulfide-rich peptides from the venom of cone snails. Along with other conopeptides, they target a wide range of membrane receptors, ion channels, and transporters, and because of their high potency and selectivity for defined subtypes of these receptors, they have attracted a great deal of attention recently as leads in drug development. However, like most peptides, conopeptides potentially suffer from the disadvantages of poor absorption, poor stability, or short biological half-lives. Recently, various chemical approaches, including residue substitutions, backbone cyclization, and disulfide-bridge modification, have been reported to increase the stability of conopeptides. These manufactured interventions add to the array of post-translational modifications that occur naturally in conopeptides. They enhance the versatility of these peptides as tools in neuroscience and as drug leads.

87 citations

Journal Article•DOI•
Crystal structures of free and antagonist-bound states of human α9 nicotinic receptor extracellular domain

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Marios Zouridakis1, Petros Giastas1, Eleftherios Zarkadas2, Dafni Chroni-Tzartou1, Piotr Bregestovski3, Socrates J. Tzartos1, Socrates J. Tzartos2 •
Pasteur Institute1, University of Patras2, French Institute of Health and Medical Research3
01 Nov 2014-Nature Structural & Molecular Biology
TL;DR: The X-ray crystal structures of the α9 ECD revealed a functionally important β7-β10 strand interaction in α9-containing nAChRs, involving their unique Thr147, a hydration pocket similar to that of mouse α1 ECD and a membrane-facing network coordinated by the invariant Arg210.
Abstract: Crystal structures of the extracellular domain of human nAChR, in its apo form and with antagonists methyllycaconitine or α-bungarotoxin bound, are presented. The structures provide insight into the channel-opening mechanism of nAChRs and their pharmacological properties.

83 citations

Journal Article•DOI•
Scanning Mutagenesis of α-Conotoxin Vc1.1 Reveals Residues Crucial for Activity at the α9α10 Nicotinic Acetylcholine Receptor

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Reena Halai1, Richard J. Clark1, Simon T. Nevin1, Jonas E. Jensen1, David J. Adams1, David J. Craik1 •
University of Queensland1
24 Jul 2009-Journal of Biological Chemistry
TL;DR: An extensive series of mutational studies are presented, providing mechanistic insight into the key residues involved in eliciting the biological function of Vc1.1 at both the rat α9α10 and the human α9/rat α10 hybrid receptor.

80 citations

Additional excerpts

  • ...Although Halai et al. (2009) designed the [S4K, N9A]Vc1....

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Journal Article•DOI•
Determination of the α-conotoxin Vc1.1 binding site on the α9α10 nicotinic acetylcholine receptor.

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Rilei Yu1, Shiva N. Kompella, David J. Adams2, David J. Craik1, Quentin Kaas1 •
University of Queensland1, RMIT University2
29 Apr 2013-Journal of Medicinal Chemistry
TL;DR: Using a combination of computational modeling and electrophysiology experiments, a single hydrogen bond formed between Vc1.1 and position 59 of the α10α9 pocket confers specificity to rat versus human α9α10 nAChRs.
Abstract: α-Conotoxin Vc1.1 specifically and potently inhibits the nicotinic acetylcholine receptor subtype α9α10 (α9α10 nAChR) and is a potential novel treatment for neuropathic pain. Here, we used a combination of computational modeling and electrophysiology experiments to determine the Vc1.1 binding site on the α9α10 nAChR. Interactions of Vc1.1 with two probable binding sites, α9α10 and α10α9, were modeled. Mutational energies calculated by assuming specific interactions in the α10α9 binding site correlated better with electrophysiological recordings than those assuming interactions with the α9α10 binding site. Two novel Vc1.1 analogues, [N9F]Vc1.1 and [N9W]Vc1.1, were predicted to have large differences in affinity between the two binding sites. Data from functional studies were consistent with computational predictions that assumed preferred binding of Vc1.1 to the α10α9 pocket. Moreover, our modeling study suggested that a single hydrogen bond formed between Vc1.1 and position 59 of the α10α9 pocket confers ...

78 citations

"α-Conotoxin Vc1.1 Structure-Activit..." refers background or methods in this paper

  • ...Previously, Yu et al. (2013) proposed the α10(+)-α9(−) interface as the favourable binding site of Vc1....

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  • ...36 Yu et al. (2018) performed a comprehensive computational modeling based on the proposed high and low Vc1....

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Journal Article•DOI•
The Efferent Medial Olivocochlear-Hair Cell Synapse

[...]

Ana Belén Elgoyhen, Eleonora Katz1•
Facultad de Ciencias Exactas y Naturales1
01 Jan 2012-Journal of Physiology-paris
TL;DR: This work reviews the literature that has enlightened knowledge concerning the intimacies of the medial olivocochlear system and concludes that hyperpolarization of hair cells follows efferent fiber activation.
Abstract: Amplification of incoming sounds in the inner ear is modulated by an efferent pathway which travels back from the brain all the way to the cochlea. The medial olivocochlear system makes synaptic contacts with hair cells, where the neurotransmitter acetylcholine is released. Synaptic transmission is mediated by a unique nicotinic cholinergic receptor composed of α9 and α10 subunits, which is highly Ca2+ permeable and is coupled to a Ca2+-activated SK potassium channel. Thus, hyperpolarization of hair cells follows efferent fiber activation. In this work we review the literature that has enlightened our knowledge concerning the intimacies of this synapse.

75 citations

Related Papers (5)
Scanning Mutagenesis of α-Conotoxin Vc1.1 Reveals Residues Crucial for Activity at the α9α10 Nicotinic Acetylcholine Receptor

[...]

24 Jul 2009-Journal of Biological Chemistry
Reena Halai, Richard J. Clark, Simon T. Nevin, Jonas E. Jensen, David J. Adams, David J. Craik 
Molecular determinants conferring the stoichiometric-dependent activity of α-conotoxins at the human α9α10 nicotinic acetylcholine receptor subtype

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07 May 2018-Journal of Medicinal Chemistry
Rilei Yu, Han-Shen Tae, Nargis Tabassum, Juan Shi, Tao Jiang, David J. Adams 
Presence of multiple binding sites on α9α10 nAChR receptors alludes to stoichiometric-dependent action of the α-conotoxin, Vc1.1.

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01 May 2014-Biochemical Pharmacology
Dinesh C. Indurthi, Elena Pera, Hye Lim Kim, Cindy Chu, Malcolm D. McLeod, J. Michael McIntosh, J. Michael McIntosh, Nathan L. Absalom, Mary Chebib 
Structure-Activity Studies Reveal the Molecular Basis for GABAB-Receptor Mediated Inhibition of High Voltage-Activated Calcium Channels by α-Conotoxin Vc1.1.

[...]

10 May 2018-ACS Chemical Biology
Mahsa Sadeghi, Bodil B. Carstens, Brid P Callaghan, James T. Daniel, Han-Shen Tae, Tracey A. O'Donnell, Joel Castro, Stuart M. Brierley, David J. Adams, David J. Craik, Richard J. Clark 
Alpha-conotoxin analogs with additional positive charge show increased selectivity towards Torpedo californica and some neuronal subtypes of nicotinic acetylcholine receptors.

[...]

01 Oct 2006-FEBS Journal
Igor E. Kasheverov, Maxim N. Zhmak, Catherine A. Vulfius, Elena V. Gorbacheva, Dmitry Y. Mordvintsev, Yuri N. Utkin, René van Elk, August B. Smit, Victor I. Tsetlin 
Frequently Asked Questions (1)
Q1. What are the contributions in "Α-conotoxin vc1.1 structure-activity relationship at the human α9α10 nicotinic acetylcholine receptor investigated by minimal side chain replacement" ?

In this paper, the authors proposed the α10 ( + ) -α9 ( − ) interface as the favorable binding site of Vc1.1 at the ( α9 ) 2 ( α10 ) 3 nAChR.