Structure of the proton-gated urea channel from the gastric pathogen Helicobacter pylori

Strugatsky, David; McNulty, Reginald; Munson, Keith; Chen, Chiung-Kuang; Soltis, S. Michael; Sachs, George; Luecke, Hartmut

doi:10.1038/nature11684

Cited by 87 publications

(104 citation statements)

References 36 publications

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“…The former cluster, closely related to that found in H. pylori, is induced by Ni 2ϩ and encodes two structural genes, a proton-gated urea channel (82), and the four standard maturation proteins. The latter cluster is inversely regulated by Ni 2ϩ and encodes only the two structural genes (83).…”

Section: Variations In Urease Activation Systemsmentioning

confidence: 99%

Biosynthesis of the Urease Metallocenter

Farrugia

Macomber

Hausinger

2013

Journal of Biological Chemistry

114

101

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Metalloenzymes often require elaborate metallocenter assembly systems to create functional active sites. The medically important dinuclear nickel enzyme urease provides an excellent model for studying metallocenter assembly. Nickel is inserted into the urease active site in a GTP-dependent process with the assistance of UreD/UreH, UreE, UreF, and UreG. These accessory proteins orchestrate apoprotein activation by delivering the appropriate metal, facilitating protein conformational changes, and possibly providing a requisite post-translational modification. The activation mechanism and roles of each accessory protein in urease maturation are the subject of ongoing studies, with the latest findings presented in this minireview.Metallocenters serve essential biological functions such as transferring electrons, stabilizing biomolecules, binding substrates, and catalyzing desirable reactions. Synthesis of these sites must be tightly controlled because simple competition between metals may lead to misincorporation with loss of function and because excess cytoplasmic concentrations of free metal ions can have toxic cellular effects. In many cases, cells have evolved elaborate metallocenter assembly systems that sequester metal cofactors from the cellular milieu, thus offering protection from adventitious reactions while ensuring the fidelity of metal insertion. In addition to maintaining metal homeostasis, these assembly systems facilitate protein conformational changes and active site modifications that are required for full enzymatic activity. Several metalloproteins have been investigated as models to understand the mechanisms and dynamics of active site assembly and the complex orchestrations of their metallocenter assembly systems. In this minireview, we discuss recent findings related to maturation of the nickel-containing enzyme urease.

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Section: Variations In Urease Activation Systemsmentioning

confidence: 99%

Biosynthesis of the Urease Metallocenter

Farrugia

Macomber

Hausinger

2013

Journal of Biological Chemistry

114

101

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“…[23][24][25][26] The central regions of such channels are narrow (accommodating several dehydrated urea molecules in single-file) and largely hydrophobic (but with a small portion of polar/charged groups), [23][24][25][26] the environments of which are somewhat similar to the model system herein (a narrow, hydrophobic SWNT with an external charge). The findings in this study might also shed light on the mechanism of biological urea channels, [23][24][25][26] such as the competitive binding between urea and water onto the polar/charged residues of the channel, and how polar/charged groups modulate urea's orientation/binding in the constricted selectivity filter. In particular, our findings suggest a potential "electrostatic gating" 8 mechanism (trapping water/urea molecules in the confined region by the charged residue) for urea channels, which complements the previously observed steric gating mechanism for the urea channel of Helicobacter pylori.…”

Section: Discussionmentioning

confidence: 94%

“…Urea is a typical organic molecule with high polarity (the most widely used value of urea's dipole moment is 4.56 D measured in dioxane 22 ). It plays an important role in the metabolism of nitrogen-containing compounds by animals, [23][24][25][26] and serves as an important raw material for the chemical industry and a common chemical denaturant of proteins. [27][28][29] Our previous molecular dynamics (MD) simulations have shown that when SWNTs are solvated in urea solutions, urea molecules can induce drying of SWNTs, 30 resulting in 1D urea wires with concerted dipole orientations and slower flipping than water wires.…”

Section: Introductionmentioning

confidence: 99%

Charge-signal multiplication mediated by urea wires inside Y-shaped carbon nanotubes

Liu

et al. 2014

The Journal of Chemical Physics

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In previous studies, we reported molecular dynamics (MD) simulations showing that single-file water wires confined inside Y-shaped single-walled carbon nanotubes (Y-SWNTs) held strong and robust capability to convert and multiply charge signals [Y. S. Tu, P. Xiu, R. Z. Wan, J. Hu, R. H. Zhou, and H. P. Fang, Proc. Natl. Acad. Sci. U.S.A. 106, 18120 (2009); Y. Tu, H. Lu, Y. Zhang, T. Huynh, and R. Zhou, J. Chem. Phys. 138, 015104 (2013)]. It is fascinating to see whether the signal multiplication can be realized by other kinds of polar molecules with larger dipole moments (which make the experimental realization easier). In this article, we use MD simulations to study the urea-mediated signal conversion and multiplication with Y-SWNTs. We observe that when a Y-SWNT with an external charge of magnitude 1.0 e (the model of a signal at the single-electron level) is solvated in 1 M urea solutions, urea can induce drying of the Y-SWNT and fill its interiors in single-file, forming Y-shaped urea wires. The external charge can effectively control the dipole orientation of the urea wire inside the main channel (i.e., the signal can be readily converted), and this signal can further be multiplied into 2 (or more) output signals by modulating dipole orientations of urea wires in bifurcated branch channels of the Y-SWNT. This remarkable signal transduction capability arises from the strong dipole-induced ordering of urea wires under extreme confinement. We also discuss the advantage of urea as compared with water in the signal multiplication, as well as the robustness and biological implications of our findings. This study provides the possibility for multiplying signals by using urea molecules (or other polar organic molecules) with Y-shaped nanochannels and might also help understand the mechanism behind signal conduction in both physical and biological systems.

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“…Two crystal structures of the UTs, dvUT [8] and UT-B [9], and one crystal structure of the proton-gated urea channel from Helicobacter pylori , HpUreI, [10] have been solved so far. These three-dimensional atomic structures have provided invaluable tools for us to understand the functional characteristics of UTs.…”

Section: Introductionmentioning

confidence: 99%

Modeling of flux, binding and substitution of urea molecules in the urea transporter dvUT

Zhang

Wang

et al. 2017

Journal of Molecular Graphics and Modelling

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Urea transporters (UTs) are transmembrane proteins that transport urea molecules across cell membranes and play a crucial role in urea excretion and water balance. Modeling the functional characteristics of UTs helps us understand how their structures accomplish the functions at the atomic level, and facilitates future therapeutic design targeting the UTs. This study was based on the crystal structure of Desulfovibrio vulgaris urea transporter (dvUT). To model the binding behavior of urea molecules in dvUT, we constructed a cooperative binding model. To model the substitution of urea by the urea analogue N,N′-dimethylurea (DMU) in dvUT, we calculated the occupation probability of DMU along the urea pore and the ratio of the occupation probabilities of DMU at the external (Sext) and internal (Sint) binding sites, and we established the mutual substitution rule for binding and substitution of urea and DMU. Based on these calculations and modelings, together with the use of the Monte Carlo (MC) method, we further modeled the urea flux in dvUT, equilibrium urea binding to dvUT, and the substitution of urea by DMU in the dvUT. Our modeling results are in good agreement with the existing experimental functional data. Furthermore, the modelings have discovered the microscopic process and mechanisms of those functional characteristics. The methods and the results would help our future understanding of the underlying mechanisms of the diseases associated with impaired UT functions and rational drug design for the treatment of these diseases.

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Structure of the proton-gated urea channel from the gastric pathogen Helicobacter pylori

Cited by 87 publications

References 36 publications

Biosynthesis of the Urease Metallocenter

Biosynthesis of the Urease Metallocenter

Charge-signal multiplication mediated by urea wires inside Y-shaped carbon nanotubes

Modeling of flux, binding and substitution of urea molecules in the urea transporter dvUT

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