A prokaryotic perspective on pentameric ligand-gated ion channel structure

Hilf, R.J.C.; Dutzler, Raimund

doi:10.1016/j.sbi.2009.07.006

Cited by 55 publications

(54 citation statements)

References 152 publications

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“…This mechanism provides the structural details of the gating reaction initiated by orthosteric agonist unbinding. We note that a similar repositioning of the β 1 -β 2 and M2-M3 loops at the EC/TM domain interface is observed when comparing the crystal structures of GLIC and ELIC (28). Also, the tertiary changes observed in helix M2 during closing are consistent with recent site-directed spin labeling and EPR measurements of GLIC (29).…”

Section: Resultssupporting

confidence: 88%

“…The distance between the C α carbons of residues P268 (on the M2-M3 loop) and V45 (at the tip of the β 1 -β 2 loop) in GluCl was used to analyze the inward displacement of the M2-M3 loop during the simulation of GluCl with and without ivermectin. These residues are optimally located at the interface between the EC and TM domains as they pack against each other in the active state, e.g., the X-ray structures of GLIC or GluCl, and move apart in the resting state, e.g., the X-ray structure of ELIC (28). We note, however, that this observable is unable to distinguish between inward and outward displacements of the M2-M3 loop nor separate radial from tangential repositioning of the interfacial loops, which all correspond to an increasing distance between the C α carbons of P268 and V45.…”

Section: ·åmentioning

confidence: 99%

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A gating mechanism of pentameric ligand-gated ion channels

Calimet

Simões

Changeux

et al. 2013

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

132

208

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Pentameric ligand-gated ion channels (pLGICs) play a central role in intercellular communication in the nervous system and are involved in fundamental processes such as attention, learning, and memory. They are oligomeric protein assemblies that convert a chemical signal into an ion flux through the postsynaptic membrane, but the molecular mechanism of gating ions has remained elusive. Here, we present atomistic molecular dynamics simulations of the prokaryotic channels from Gloeobacter violaceus (GLIC) and Erwinia chrysanthemi (ELIC), whose crystal structures are thought to represent the active and the resting states of pLGICs, respectively, and of the eukaryotic glutamate-gated chloride channel from Caenorhabditis elegans (GluCl), whose openchannel structure was determined complexed with the positive allosteric modulator ivermectin. Structural observables extracted from the trajectories of GLIC and ELIC are used as progress variables to analyze the time evolution of GluCl, which was simulated in the absence of ivermectin starting from the structure with bound ivermectin. The trajectory of GluCl with ivermectin removed shows a sequence of structural events that couple agonist unbinding from the extracellular domain to ion-pore closing in the transmembrane domain. Based on these results, we propose a structural mechanism for the allosteric communication leading to deactivation/activation of the GluCl channel. This model of gating emphasizes the coupling between the quaternary twisting and the opening/closing of the ion pore and is likely to apply to other members of the pLGIC family.neurotransmitter receptors | chemo-electrical transduction | ion channel gating P entameric ligand-gated ion channels (pLGICs) mediate intercellular communication in the brain by converting a chemical signal, typically a local increase in the extracellular concentration of neurotransmitter, into an electrical signal, which is generated by an ion flux through the postsynaptic membrane (1). Understanding their function at an atomic level of detail is likely to be useful for the development of drug therapies against a range of disorders, including nicotine addiction, Alzheimer's disease, schizophrenia, and depression (2).pLGICs are oligomeric membrane proteins with a fivefold pseudosymmetry axis perpendicular to the membrane. Each subunit consists of an extracellular (EC) domain that contains the ligand-binding site and a transmembrane (TM) ion-pore domain. The agonist binding site is located at the boundary between subunits in the EC domain whereas the ion pore is formed by the transmembrane helices M2, which differentiate axial cationic and anionic channels (Fig. 1). An essential element of the mechanism is that these topologically distinct domains are allosterically coupled to each other (3, 4).Electrophysiology analysis of pLGICs first showed that the rapid delivery of agonist promotes fast opening of the channel whereas prolonged applications lead to a slow decrease of the response amplitude or "desensitization" (5). Several kineti...

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Section: Resultssupporting

confidence: 88%

Section: ·åmentioning

confidence: 99%

A gating mechanism of pentameric ligand-gated ion channels

Calimet

Simões

Changeux

et al. 2013

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

132

208

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“…We foresee therefore two possible activation mechanisms for KtrAB (see also Supplementary Discussion 27,28 ). For model 1, the asymmetric KtrA contraction/expansion occurs along the diagonal defined by the lateral contacts (Fig.…”

Section: Implications For Ktrab Activationmentioning

confidence: 99%

The structure of the KtrAB potassium transporter

Vieira-Pires

Szöllősi

Morais-Cabral

2013

Nature

106

164

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In bacteria, archaea, fungi and plants the Trk, Ktr and HKT ion transporters are key components of osmotic regulation, pH homeostasis and resistance to drought and high salinity. These ion transporters are functionally diverse: they can function as Na + or K + channels and possibly as cation/K + symporters. They are closely related to potassium channels both at the level of the membrane protein and at the level of the cytosolic regulatory domains. Here we describe the crystal structure of a Ktr K + transporter, the KtrAB complex from Bacillus subtilis. The structure shows the dimeric membrane protein KtrB assembled with a cytosolic octameric KtrA ring bound to ATP, an activating ligand. A comparison between the structure of KtrAB-ATP and the structures of the isolated fulllength KtrA protein with ATP or ADP reveals a ligand-dependent conformational change in the octameric ring, raising new ideas about the mechanism of activation in these transporters.The Trk/Ktr/HKT superfamily of ion transporters includes the Trk, Ktr and HKT transporter families 1 . These transporters are closely related to the superfamily of tetrameric cation channels 2-4 , which includes potassium, sodium and calcium channels. The membrane proteins in both superfamilies share the same architecture 2,5-9 : four subunits or repeats, each with the TM-P loop-TM (where TM indicates transmembrane helix) structural motif first seen in the KcsA potassium channel structure 10 , assemble to form an ion pore with a 'selectivity filter' along its central axis. In addition, the cytosolic regulatory proteins of the Trk and Ktr transporters and of the MthK 11,12 and large-conductance Ca 2+ -gated (BK) K + channels [13][14][15] are RCK (regulate conductance of K+) domains.Ktr ion transporters are crucial K + transport systems in some bacteria 16,17 , with a role in resistance to osmotic stress and high salinity by mediating the early uptake of K + (refs 16, 18). The Ktr ion transporters are composed of two essential components 3,16 : a membrane protein (KtrB or KtrD) and a cytosolic regulatory protein (KtrA or KtrC). Studies with cells show that Ktr proteins 8,19 transport K + but are also permeable to Na + , and that K + transport is ATP 20 and Na + dependent 5,8,18 . Furthermore, it has been shown that truncated KtrA forms octameric rings 21,22 and that KtrB assembles as homodimers 6,21 . The structures described here clarify the molecular basis of some of these properties as well as the structural relationship between these transporters and ion channels.

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“…The hydrosulfide channel HSC closely follows this architectural principle (9). Distinct channels are seen in each individual protomer, in contrast to ligand-gated ion channels in which all subunits form a common, central pore (23). Direct electrophysiological measurements of S. typhimurium FocA (StFocA) show that StFocA acts as a channel for a range of monovalent anions at high pH values (24) and is gated in a pHdependent manner (21).…”

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confidence: 99%

Structural and functional characterization of the nitrite channel NirC from Salmonella typhimurium

Lü

Schwarzer

et al. 2012

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

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) is a central intermediate in the nitrogen metabolism of microorganisms and plants, and is used as a cytotoxin by macrophages as part of the innate immune response. The bacterial membrane protein NirC acts as a specific channel to facilitate the transport of nitrite anions across lipid bilayers for cytoplasmic detoxification. Despite NirC's importance in nitrogen metabolism and in the pathogenicity of enteric bacteria, available biochemical data are scarce. Here we present a functional and structural characterization of NirC from Salmonella typhimurium by lipid bilayer electrophysiology and X-ray crystallography. NirC is a pentameric member of the formate/nitrite transporter family of membrane proteins that operates as a channel with high conductance. Single-channel measurements reveal fast and slow gating events but, in contrast to the related FocA formate channel, no pH-dependent gating. A 2.4Å crystal structure of NirC at pH 5 shows similarity to FocA and aquaporins, but lacks the structural asymmetry observed in the formate channel at similarly low pH. Resolved water molecules in the protomers suggest a transport mechanism that also permits a facultative NO 2 − /H + symport.ion channels | protein crystallography | planar lipid bilayer

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A prokaryotic perspective on pentameric ligand-gated ion channel structure

Cited by 55 publications

References 152 publications

A gating mechanism of pentameric ligand-gated ion channels

A gating mechanism of pentameric ligand-gated ion channels

The structure of the KtrAB potassium transporter

Structural and functional characterization of the nitrite channel NirC from Salmonella typhimurium

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