Robustness of the Rotary Catalysis Mechanism of F1-ATPase

Watanabe, Rikiya; Matsukage, Yuki; Yukawa, Ayako; Tabata, Kazuhito V.; Noji, Hiroyuki

doi:10.1074/jbc.m114.569905

Cited by 10 publications

(13 citation statements)

References 50 publications

(59 reference statements)

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“…This means that the interaction with the base structure of nucleotide is critical for the enhancement of binding, but not for torque generation. This is in contrast to the impact of mutation at the phosphate-binding residues, which largely impaired the kinetic power as well as torque generation (Arai et al 2014; Watanabe et al 2014). …”

Section: Robustnessmentioning

confidence: 94%

“…Mutagenesis studies also showed that, when these residues are substituted with non-charged residues such as alanine, the catalytic power is abolished (Senior and Al-Shawi 1992; Yagi et al 2009). Alanine mutants at these residues were re-investigated in rotation assay systems to confirm their critical role in catalysis (Watanabe et al 2014). Against all expectations, all of the mutants showed unidirectional rotation.…”

Section: Robustnessmentioning

confidence: 99%

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Catalytic robustness and torque generation of the F1-ATPase

2017

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The F1-ATPase is the catalytic portion of the FoF1 ATP synthase and acts as a rotary molecular motor when it hydrolyzes ATP. Two decades have passed since the single-molecule rotation assay of F1-ATPase was established. Although several fundamental issues remain elusive, basic properties of F-type ATPases as motor proteins have been well characterized, and a large part of the reaction scheme has been revealed by the combination of extensive structural, biochemical, biophysical, and theoretical studies. This review is intended to provide a concise summary of the fundamental features of F1-ATPases, by use of the well-described model F1 from the thermophilic Bacillus PS3 (TF1). In the last part of this review, we focus on the robustness of the rotary catalysis of F1-ATPase to provide a perspective on the re-designing of novel molecular machines.

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Section: Robustnessmentioning

confidence: 94%

Section: Robustnessmentioning

confidence: 99%

Catalytic robustness and torque generation of the F1-ATPase

2017

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“…Decades later, the first single molecule experiment showed the rotary motion of the stalk as F 1 performed its ATP hydrolysis process (Noji et al 1997). Since then, various rotary-chemical aspects of the F 1 motor have been revealed through other important studies, where the rotational path has been traced out in further details and the average torque generated by the system has been calculated (Adachi et al 2007; Masaike et al 2008; Panke et al 2001; Watanabe et al 2014; Yasuda et al 2001). …”

Section: The Fof1 Atp Synthasementioning

confidence: 99%

The FOF1 ATP synthase: from atomistic three-dimensional structure to the rotary-chemical function

Mukherjee

Warshel

2017

Photosynth Res

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Molecular motors are multi-subunit complexes that are indispensable for accomplishing various tasks of the living cells. One such molecular motor is the FOF1 ATP synthase that synthesizes ATP at the expense of the membrane proton gradient. Elucidating the molecular origin of the motor function is challenging despite significant advances in various experimental fields. Currently atomic simulations of whole motor complexes cannot reach to functionally relevant time scales that extend beyond the millisecond regime. Moreover, to reveal the underlying molecular origin of the function, one must model the coupled chemical and conformational events using physically and chemically meaningful multiscaling techniques. In this review, we discuss our approach to model the action of the F1 and FO molecular motors, where emphasis is laid on elucidating the molecular origin of the driving force that leads to directional rotation at the expense of ATP hydrolysis or proton gradients. We have used atomic structures of the motors and used hierarchical multiscaling techniques to generate low dimensional functional free energy surfaces of the complete mechano-chemical process. These free energy surfaces were studied further to calculate important characteristics of the motors, such as, rotational torque, temporal dynamics, occurrence of intermittent dwell states, etc. We also studied the result of mutating various parts of the motor domains and our observations correspond very well with the experimental findings. Overall, our studies have generated a cumulative understanding of the motor action, and especially highlight the crucial role of electrostatics in establishing the mechano-chemical coupling.

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“…Successful implementation of this new methodology will lead to the development of the next generation of potent drugs. In fact the first drug approved to treat multidrug-resistant tuberculosis, bedaquiline [4], is acting on the ATP synthase which is a multisubunit biomotor [100-111]. Treating multidrug-resistant tuberculosis had been very challenging previously.…”

Section: Expert Opinionmentioning

confidence: 99%

Discovery of a new method for potent drug development using power function of stoichiometry of homomeric biocomplexes or biological nanomotors

Vieweger

Zhao

et al. 2015

Expert Opinion on Drug Delivery

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Introduction Multidrug resistance and the appearance of incurable diseases inspire the quest for potent therapeutics. Areas Covered We review a new methodology in designing potent drugs by targeting multi-subunit homomeric biological motors, machines, or complexes with Z>1 and K=1, where Z is the stoichiometry of the target, and K is the number of drugged subunits required to block the function of the complex. The condition is similar to a series, electrical circuit of Christmas decorations; failure of one light bulb causes the entire lighting system to lose power. In most multisubunit, homomeric biological systems, a sequential coordination or cooperative action mechanism is utilized, thus K equals 1. Drug inhibition depends on the ratio of drugged to nondrugged complexes. When K=1, and Z>1, the inhibition effect follows a power law with respect to Z, leading to enhanced drug potency. The hypothesis that the potency of drug inhibition depends on the stoichiometry of the targeted biological complexes was recently quantified by Yang-Hui's Triangle (or binomial distribution), and proved using a highly sensitive in vitro phi29 viral DNA packaging system. Examples of targeting homomeric bio-complexes with high stoichiometry for potent drug discovery are discussed. Expert Opinion Biomotors with multiple subunits are widespread in viruses, bacteria, and cells, making this approach generally applicable in the development of inhibition drugs with high efficiency.

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Robustness of the Rotary Catalysis Mechanism of F1-ATPase

Cited by 10 publications

References 50 publications

Catalytic robustness and torque generation of the F1-ATPase

Catalytic robustness and torque generation of the F1-ATPase

The FOF1 ATP synthase: from atomistic three-dimensional structure to the rotary-chemical function

Discovery of a new method for potent drug development using power function of stoichiometry of homomeric biocomplexes or biological nanomotors

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