X-ray crystal structure of voltage-gated proton channel

Takeshita, Keizo; Sakata, Souhei; Yamashita, Eiki; Fujiwara, Yuichiro; Kawanabe, Akira; Kurokawa, Tetsuji; Okochi, Yoshifumi; Matsuda, M.; Narita, Hiroko; Okamura, Yasushi; Nakagawa, Atsushi

doi:10.1038/nsmb.2783

Cited by 184 publications

(344 citation statements)

References 62 publications

Supporting

Mentioning

327

Contrasting

Unclassified

Order By: Relevance

“…While Hv1 is ubiquitously expressed and plays an important role in a number of physiological processes such as the innate immune system, apoptosis, and cancer metastasis, the presence of Hv1 in human spermatozoa was intriguing. Hv1 is not a true ion channel, but rather a strange mix between a transporter and an ion channel without the pore, that provides rapid movement of protons across a lipid bilayer via a voltage-gated mechanism [116][117][118].…”

Section: Mechanisms Of Proton Extrusion From Mammalian Spermmentioning

confidence: 99%

“…The latter occurs once the plug is removed by a voltage-dependent rearrangement of TMs and is followed by insertion of the protonatable residues in the center of the channel [116]. The recent crystal structure of the Hv1 in resting state sheds [118] light on the possible mechanism of H + permeation, suggesting that a combination of two hydrophobic plugs and a protonatable aspartate is required for proton movement. However, Hv1 structure in the open state is also required to completely understand this process.…”

Section: Hv1: Principles Of Proton Permeationmentioning

confidence: 99%

See 1 more Smart Citation

Flagellar ion channels of sperm: similarities and differences between species

et al. 2015

View full text Add to dashboard Cite

a b s t r a c tMotility and fertilization potential of mammalian sperm are regulated by ion homeostasis which in turn is under tight control of ion channels and transporters. Sperm intracellular pH, membrane voltage and calcium concentration ([Ca 2+ ] i ) are all important for sperm activity within the female reproductive tract. While all mammalian sperm are united in their goal to find and fertilize an egg, the molecular mechanisms they utilize for this purpose are diverse and differ between species especially on the level of ion channels. Recent direct recording from sperm cells of different species indicate the differences between rodent, non-human primate, ruminant, and human sperm on the basic levels of their ion channel regulation. In this review we summarize the current knowledge about ion channel diversity of the animal kingdom and concentrate our attention on flagellar ion channels of mammalian sperm.

show abstract

Section: Mechanisms Of Proton Extrusion From Mammalian Spermmentioning

confidence: 99%

Section: Hv1: Principles Of Proton Permeationmentioning

confidence: 99%

Flagellar ion channels of sperm: similarities and differences between species

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Almost simultaneously reported, the structures of the proton channel Hv1 and the voltage-sensitive phosphatase, were solved by X-ray diffraction. 8,31,32 Remarkably, the structure of CiVSP was obtained in putative activated and resting states, while the structure of Hv1 seems to be of a resting state.…”

Section: Introductionmentioning

confidence: 97%

Functional diversity of potassium channel voltage-sensing domains

Islas¹

2016

Channels

View full text Add to dashboard Cite

Voltage-gated potassium channels or Kv's are membrane proteins with fundamental physiological roles. They are composed of 2 main functional protein domains, the pore domain, which regulates ion permeation, and the voltage-sensing domain, which is in charge of sensing voltage and undergoing a conformational change that is later transduced into pore opening. The voltagesensing domain or VSD is a highly conserved structural motif found in all voltage-gated ion channels and can also exist as an independent feature, giving rise to voltage sensitive enzymes and also sustaining proton fluxes in proton-permeable channels. In spite of the structural conservation of VSDs in potassium channels, there are several differences in the details of VSD function found across variants of Kvs. These differences are mainly reflected in variations in the electrostatic energy needed to open different potassium channels. In turn, the differences in detailed VSD functioning among voltage-gated potassium channels might have physiological consequences that have not been explored and which might reflect evolutionary adaptations to the different roles played by Kv channels in cell physiology.

show abstract

“…These discoveries, and the ensuing potential therapeutic strategies, ignited extensive searches for effective Hv1 inhibitors; these efforts led to the identification of positively charged binders of the activated state (8,29,30). The lack of available experimental structures, only recently overcome by the discovery of the X-ray structure (31) of mouse Hv1, has motivated the generation of several comparative homology models using various VGICs as templates (32)(33)(34)(35)(36)(37)(38). Nonetheless, none of these studies focused on a systematic characterization of Hv1 as a pharmacological target using a structure-based approach for drug design.…”

mentioning

confidence: 99%

On the role of water density fluctuations in the inhibition of a proton channel

Gianti

Delemotte

Klein

et al. 2016

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

View full text Add to dashboard Cite

Hv1 is a transmembrane four-helix bundle that transports protons in a voltage-controlled manner. Its crucial role in many pathological conditions, including cancer and ischemic brain damage, makes Hv1 a promising drug target. Starting from the recently solved crystal structure of Hv1, we used structural modeling and molecular dynamics simulations to characterize the channel's most relevant conformations along the activation cycle. We then performed computational docking of known Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and analogs. Although salt-bridge patterns and electrostatic potential profiles are well-defined and distinctive features of activated versus nonactivated states, the water distribution along the channel lumen is dynamic and reflects a conformational heterogeneity inherent to each state. In fact, pore waters assemble into intermittent hydrogen-bonded clusters that are replaced by the inhibitor moieties upon ligand binding. The entropic gain resulting from releasing these conformationally restrained waters to the bulk solvent is likely a major contributor to the binding free energy. Accordingly, we mapped the water density fluctuations inside the pore of the channel and identified the regions of maximum fluctuation within putative binding sites. Two sites appear as outstanding: One is the already known binding pocket of 2GBI, which is accessible to ligands from the intracellular side; the other is a site located at the exit of the proton permeation pathway. Our analysis of the waters confined in the hydrophobic cavities of Hv1 suggests a general strategy for drug discovery that can be applied to any ion channel.Hv1 | drug design | pore waters | binding site discovery | confined waters

show abstract

X-ray crystal structure of voltage-gated proton channel

Cited by 184 publications

References 62 publications

Flagellar ion channels of sperm: similarities and differences between species

Flagellar ion channels of sperm: similarities and differences between species

Functional diversity of potassium channel voltage-sensing domains

On the role of water density fluctuations in the inhibition of a proton channel

Contact Info

Product

Resources

About