GTP Analogue Inhibits Polymerization and GTPase Activity of the Bacterial Protein FtsZ without Affecting Its Eukaryotic Homologue Tubulin

Läppchen, Tilman; Hartog, Aloysius F.; Pinas, Victorine A.; Koomen, Gerrit‐Jan; Blaauwen, Tanneke den

doi:10.1021/bi047297o

Cited by 72 publications

(52 citation statements)

References 37 publications

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“…As shown in Table 1, the k cat (0.75 min Ϫ1 ) for GTP hydrolysis by B. subtilis FtsZ is comparable with that reported previously (22); however, it is lower than those reported for E. coli FtsZ (12, 29 -32). Moreover, the K m (39.45 M) is also comparable with that reported for E. coli FtsZ (29). In the presence of EzrA, the k cat for GTP hydrolysis by B. subtilis FtsZ increased about 1.67-fold (1.25 min Ϫ1 /0.75 min Ϫ1 ), further confirming that EzrA is able to enhance the GTP hydrolysis rate of FtsZ.…”

Section: Ezra Enhances the Gtpase Activity Of Ftsz-the Increase In Bisupporting

confidence: 82%

Mechanism of Regulation of Prokaryotic Tubulin-like GTPase FtsZ by Membrane Protein EzrA

Chung

Hsu

Yeh

et al. 2007

Journal of Biological Chemistry

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At initiation of cell division, FtsZ, a tubulin-like GTPase, assembles into a so-called Z-ring structure at the site of division. The formation of Z ring is negatively regulated by EzrA, which ensures only one ring at the midcell per cell cycle. The mechanism leading to the negative regulation of Z-ring formation by EzrA has been analyzed. Our data reveal that the interaction between EzrA and FtsZ not only reduces the GTP-binding ability of FtsZ but also accelerates the rate of GTP hydrolysis, both of which are unfavorable for the polymerization of FtsZ. Moreover, the acceleration in rate of GTP hydrolysis by EzrA is attributed to stabilization of the transition state for GTP hydrolysis and reduction in the affinity of GDP for FtsZ. Clearly, EzrA is able to modify the GTP hydrolysis cycle of FtsZ. On the basis of these results, a model for how EzrA acts to negatively regulate Z-ring formation is proposed.

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Section: Ezra Enhances the Gtpase Activity Of Ftsz-the Increase In Bisupporting

confidence: 82%

Mechanism of Regulation of Prokaryotic Tubulin-like GTPase FtsZ by Membrane Protein EzrA

Chung

Hsu

Yeh

et al. 2007

Journal of Biological Chemistry

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“…Many six-or eightsubstituted GTP and ATP analogs are being synthesized to act as specific inhibitors. [32][33][34] Bookser et al correlated the binding affinities of such compounds to their anti/syn preference in water as obtained by 1 H NMR. Most adenosine analogs prefer the syn conformations, but the compounds with the highest adenosine kinase inhibitor potency all prefer the anti conformation.…”

Section: Discussionmentioning

confidence: 99%

Hamiltonian replica exchange molecular dynamics using soft-core interactions

Hritz

Oostenbrink

2008

The Journal of Chemical Physics

132

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To overcome the problem of insufficient conformational sampling within biomolecular simulations, we have developed a novel Hamiltonian replica exchange molecular dynamics ͑H-REMD͒ scheme that uses soft-core interactions between those parts of the system that contribute most to high energy barriers. The advantage of this approach over other H-REMD schemes is the possibility to use a relatively small number of replicas with locally larger differences between the individual Hamiltonians. Because soft-core potentials are almost the same as regular ones at longer distances, most of the interactions between atoms of perturbed parts will only be slightly changed. Rather, the strong repulsion between atoms that are close in space, which in many cases results in high energy barriers, is weakened within higher replicas of our proposed scheme. In addition to the soft-core interactions, we proposed to include multiple replicas using the same Hamiltonian/level of softness. We have tested the new protocol on the GTP and 8-Br-GTP molecules, which are known to have high energy barriers between the anti and syn conformation of the base with respect to the sugar moiety. During two 25 ns MD simulations of both systems the transition from the more stable to the less stable ͑but still experimentally observed͒ conformation is not seen at all. Also temperature REMD over 50 replicas for 1 ns did not show any transition at room temperature. On the other hand, more than 20 of such transitions are observed in H-REMD using six replicas ͑at three different Hamiltonians͒ during 6.8 ns per replica for GTP and 12 replicas ͑at six different Hamiltonians͒ during 8.7 ns per replica for 8-Br-GTP. The large increase in sampling efficiency was obtained from an optimized H-REMD scheme involving soft-core potentials, with multiple simulations using the same level of softness. The optimization of the scheme was performed by fast mimicking ͓J. Hritz and C. Oostenbrink, J. Chem. Phys. 127, 204104 ͑2007͔͒.

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“…It inhibits FtsZ polymerization but does not affect tubulin polymerization. 17 GTP and 8-Br-GTP both have two stable orientations of the base toward the sugar: anti and syn ͑Fig. 1͒.…”

Section: Introductionmentioning

confidence: 99%

Optimization of replica exchange molecular dynamics by fast mimicking

Hritz¹,

Oostenbrink²

2007

The Journal of Chemical Physics

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We present an approach to mimic replica exchange molecular dynamics simulations ͑REMD͒ on a microsecond time scale within a few minutes rather than the years, which would be required for real REMD. The speed of mimicked REMD makes it a useful tool for "testing" the efficiency of different settings for REMD and then to select those settings, that give the highest efficiency. We present an optimization approach with the example of Hamiltonian REMD using soft-core interactions on two model systems, GTP and 8-Br-GTP. The optimization process using REMD mimicking is very fast. Optimization of Hamiltonian-REMD settings of GTP in explicit water took us less than one week. In our study we focus not only on finding the optimal distances between neighboring replicas, but also on finding the proper placement of the highest level of softness. In addition we suggest different REMD simulation settings at this softness level. We allow several replicas to be simulated at the same Hamiltonian simultaneously and reduce the frequency of switching attempts between them. This approach allows for more efficient conversions from one stable conformation to the other.

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GTP Analogue Inhibits Polymerization and GTPase Activity of the Bacterial Protein FtsZ without Affecting Its Eukaryotic Homologue Tubulin

Cited by 72 publications

References 37 publications

Mechanism of Regulation of Prokaryotic Tubulin-like GTPase FtsZ by Membrane Protein EzrA

Mechanism of Regulation of Prokaryotic Tubulin-like GTPase FtsZ by Membrane Protein EzrA

Hamiltonian replica exchange molecular dynamics using soft-core interactions

Optimization of replica exchange molecular dynamics by fast mimicking

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