Rational Understanding of Nicotinic Receptors Drug Binding

Grütter, Thomas; Novère, Nicolas Le; Changeux, Jean‐Pierre

doi:10.2174/1568026043451177

Cited by 27 publications

(19 citation statements)

References 39 publications

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“…It has been hypothesized, based on results from mutational studies, that the Zn 2+ binding site resides at the interface between P2X 2 subunits on homomeric channels [221]. To date, this is the only evidence for a regulatory intersubunit binding site for any factor on a P2X channel, although intersubunit binding sites have been demonstrated to be present in other ion channels including GABA A , glycine, and nicotinic receptors (for discussion, see [47,113,268]). P2X 2 channels are known to dilate after prolonged agonist activation, a characteristic shared by homomeric P2X 4 , P2X 5 , and P2X 7 channels [166,307].…”

Section: Activationmentioning

confidence: 99%

Pharmacology of P2X channels

Gever¹,

Cockayne

Dillon

et al. 2006

Pflugers Arch - Eur J Physiol

280

277

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Significant progress in understanding the pharmacological characteristics and physiological importance of homomeric and heteromeric P2X channels has been achieved in recent years. P2X channels, gated by ATP and most likely trimerically assembled from seven known P2X subunits, are present in a broad distribution of tissues and are thought to play an important role in a variety of physiological functions, including peripheral and central neuronal transmission, smooth muscle contraction, and inflammation. The known homomeric and heteromeric P2X channels can be distinguished from each other on the basis of pharmacological differences when expressed recombinantly in cell lines, but whether this pharmacological classification holds true in native cells and in vivo is less well-established. Nevertheless, several potent and selective P2X antagonists have been discovered in recent years and shown to be efficacious in various animal models including those for visceral organ function, chronic inflammatory and neuropathic pain, and inflammation. The recent advancement of drug candidates targeting P2X channels into human trials, confirms the medicinal exploitability of this novel target family and provides hope that safe and effective medicines for the treatment of disorders involving P2X channels may be identified in the near future.

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Section: Activationmentioning

confidence: 99%

Pharmacology of P2X channels

Gever¹,

Cockayne

Dillon

et al. 2006

Pflugers Arch - Eur J Physiol

280

277

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“…There are two main subtypes of nAChRs present in the nervous system: the neuronal type receptors, found in the central nervous system and on all autonomic ganglia, and the neuromuscular type receptors, present in the neuromuscular junctions of somatic muscles. Recently, neuronal nAChRs such as a4b2 and a7 have emerged as attractive therapeutic targets for the treatment of pain, cognitive impairment, neurodegenerative disease, schizophrenia, epilepsy, anxiety, and depression because of their modulatory influence in the central nervous system [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors

Cheng¹,

Wang²,

Grant³

et al. 2005

PLoS Comp Biol

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The initial coupling between ligand binding and channel gating in the human a7 nicotinic acetylcholine receptor (nAChR) has been investigated with targeted molecular dynamics (TMD) simulation. During the simulation, eight residues at the tip of the C-loop in two alternating subunits were forced to move toward a ligand-bound conformation as captured in the crystallographic structure of acetylcholine binding protein (AChBP) in complex with carbamoylcholine. Comparison of apo-and ligand-bound AChBP structures shows only minor rearrangements distal from the ligandbinding site. In contrast, comparison of apo and TMD simulation structures of the nAChR reveals significant changes toward the bottom of the ligand-binding domain. These structural rearrangements are subsequently translated to the pore domain, leading to a partly open channel within 4 ns of TMD simulation. Furthermore, we confirmed that two highly conserved residue pairs, one located near the ligand-binding pocket (Lys145 and Tyr188), and the other located toward the bottom of the ligand-binding domain (Arg206 and Glu45), are likely to play important roles in coupling agonist binding to channel gating. Overall, our simulations suggest that gating movements of the a7 receptor may involve relatively small structural changes within the ligand-binding domain, implying that the gating transition is energy-efficient and can be easily modulated by agonist binding/unbinding.

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“…The general structure of the agonist binding site, also called the orthosteric binding site (in contrast to an allosteric binding site), in nAChRs has been outlined by homology with AChBP (187)(188)(189)(190). General principles, however, do not explain the diversity of ligand interactions and functional behaviors observed with the diversity of subtypes of nAChRs.…”

Section: How Do Ligands Bind To Nachrs?mentioning

confidence: 99%

Structural answers and persistent questions about how nicotinic receptors work

Wells¹

2008

Front Biosci

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The electron diffraction structure of nicotinic acetylcholine receptor (nAChR) from Torpedo marmorata and the X-ray crystallographic structure of acetylcholine binding protein (AChBP) are providing new answers to persistent questions about how nAChRs function as biophysical machines and as participants in cellular and systems physiology. New high-resolution information about nAChR structures might come from advances in crystallography and NMR, from extracellular domain nAChRs as high fidelity models, and from prokaryotic nicotinoid proteins. At the level of biophysics, structures of different nAChRs with different pharmacological profiles and kinetics will help describe how agonists and antagonists bind to orthosteric binding sites, how allosteric modulators affect function by binding outside these sites, how nAChRs control ion flow, and how large cytoplasmic domains affect function. At the level of cellular and systems physiology, structures of nAChRs will help characterize interactions with other cellular components, including lipids and trafficking and signaling proteins, and contribute to understanding the roles of nAChRs in addiction, neurodegeneration, and mental illness. Understanding nAChRs at an atomic level will be important for designing interventions for these pathologies. KeywordsAcetylcholine; Addiction; Neurodegeneration; Nicotine; Protein Design; Protein Folding; Protein Structure; Cys-Loop Receptors; Review INTRODUCTIONNicotinic acetylcholine receptors (nAChRs) are integral-membrane, neurotransmitteractivated ion channels in the central and peripheral nervous systems that participate in signal transmission associated with the physiological release of acetylcholine (1). As cationselective ion channels, they depolarize transmembrane voltage when they transition from the closed resting state to the open cation-conducting state by binding agonist. Continued exposure to agonist causes transition from the open state to the closed desensitized state. More than four decades of research have answered many structural questions about nAChRs. Reviews published across these decades reveal the progression of questions and answers (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Current understanding of the structural basis of how nAChRs work is relatively advanced compared to other areas of ion channel biophysics (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Despite this level of understanding, however, questions persist, not only about biophysical properties but also about the structural basis of how nAChRs affect cellular and systems physiology (28). NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptBy reviewing research literature published primarily between 2003 and mid-2007, the goals of this review are to describe the current state of understanding of the structures of nAChRs and to describe questions for which atomic-level structural answers still await. WHICH STRUCTURAL FEATURES DEFINE NACHRS AND OTHER CYS-LOOP RECEPTORS?Mammalian genomes contain 16 nAChR subunits ...

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Rational Understanding of Nicotinic Receptors Drug Binding

Cited by 27 publications

References 39 publications

Pharmacology of P2X channels

Pharmacology of P2X channels

Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors

Structural answers and persistent questions about how nicotinic receptors work

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