Torque Generation Mechanism of F1-ATPase upon NTP Binding

Arai, Hidenobu; Yukawa, Ayako; Iwatate, Ryu J.; Kamiya, Mako; Watanabe, Rikiya; Urano, Yasuteru; Noji, Hiroyuki

doi:10.1016/j.bpj.2014.05.016

Cited by 15 publications

(16 citation statements)

References 45 publications

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“…This lies close to the experimentally observed average torque range of 40-50 pN nm (6,20). Note that our torque calculation is based on the maximum free energy difference between the initial and final states (0°and 120°) without considering the limiting factor of the effect of the viscous drag on the probe used to measure the experimental torque (6,10,20,21). Hence, our values most likely represent the upper limit of the torque.…”

Section: Resultssupporting

confidence: 83%

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Dissecting the role of the γ-subunit in the rotary–chemical coupling and torque generation of F ₁ -ATPase

Mukherjee

Warshel

2015

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

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Unraveling the molecular nature of the conversion of chemical energy (ATP hydrolysis in the α/β-subunits) to mechanical energy and torque (rotation of the γ-subunit) in F 1 -ATPase is very challenging. A major part of the challenge involves understanding the rotarychemical coupling by a nonphenomenological structure-energy description, while accounting for the observed torque generated on the γ-subunit and its change due to mutation of this unit. Here we extend our previous study that used a coarse-grained model of the F 1 -ATPase to generate a structure-based free energy landscape of the rotary-chemical process. Our quantitative analysis of the landscape reproduced the observed torque for the wild-type enzyme. In doing so, we found that there are several possibilities of torque generation from landscapes with various shapes and demonstrated that a downhill slope along the chemical coordinate could still result in negligible torque, due to ineffective coupling of the chemistry to the γ-subunit rotation. We then explored the relationship between the functionality and the underlying sequence through systematic examination of the effect of various parts of the γ-subunit on free energy surfaces of F 1 -ATPase. Furthermore, by constructing several types of γ-deletion systems and calculating the corresponding torque generation, we gained previously unknown insights into the molecular nature of the F 1 -ATPase rotary motor. Significantly, our results are in excellent agreement with recent experimental findings and indicate that the rotary-chemical coupling is primarily established through electrostatic effects, although specific contacts through γ-ionizable residue side chains are not essential for establishing the basic features of the coupling. G aining a detailed understanding of the biological conversion of ATP to ADP is crucial for understanding the nature of biological energy transduction and for practical understanding of the action of molecular motors (1, 2). At present it seems that some of the details of this process have remained a major puzzle (1-6). One of the main open questions is associated with the understanding of the way the chemical energy is converted to conformational changes and to work. This challenge become quite exciting in view of the remarkable progress made by singlemolecule studies that directly visualized the unidirectional rotation of the γ-subunit (7-9). One of the intriguing findings of these studies has been the discovery of the catalytic dwells (7) where the γ-subunit rotation stops intermittently during the ligand binding and catalytic phases occurring in the α/β-subunits. Another recent discovery is the finding that the rotational process continues in the right direction even when major parts of the γ-subunit are removed (10, 11). These latest findings seem to present a problem for models that have postulated a steric mechanism as the driving force for torque generation.Molecular dynamics simulations aimed at understanding the rotary-chemical coupling (12-15) have been instructive,...

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Section: Resultssupporting

confidence: 83%

“…4, where overcoming the challenge of evaluating this equation by the LD simulations is mainly academic. Of course, trying to obtain the torque from experimental studies is a completely different issue (6,20,21). .…”

Section: Background and Conceptual Issuesmentioning

confidence: 99%

Dissecting the role of the γ-subunit in the rotary–chemical coupling and torque generation of F ₁ -ATPase

Mukherjee

Warshel

2015

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

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“…Arginine finger and catalytic glutamic acid residue mutants also resulted in a torque reduction of 50%. This is in contrast to the impact of chemical modification of ATP on torque generation (Arai et al 2014). The F 1 has broad nucleotide specificity, hydrolyzing other nucleotides: GTP, CTP, and UTP, albeit with changes in the catalysis rate.…”

Section: Robustnessmentioning

confidence: 82%

“…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: 93%

Catalytic robustness and torque generation of the F1-ATPase

2017

Self Cite

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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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“…In fact, the first drug approved to treat multidrug-resistant tuberculosis, bedaquiline (104), acts on the ATP synthase, which is a multisubunit biomotor (Fig. 4C) (105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116). Although this drug's inventors were not aware of the concept of targeting multisubunit complexes, its success supports the notion of using the multisubunit complex as a potent drug target.…”

Section: Perspectivesmentioning

confidence: 99%

Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism

Zhao

Chelikani

et al. 2016

J Virol

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The intracellular parasitic nature of viruses and the emergence of antiviral drug resistance necessitate the development of new potent antiviral drugs. Recently, a method for developing potent inhibitory drugs by targeting biological machines with high stoichiometry and a sequential-action mechanism was described. Inspired by this finding, we reviewed the development of antiviral drugs targeting viral DNA-packaging motors. Inhibiting multisubunit targets with sequential actions resembles breaking one bulb in a series of Christmas lights, which turns off the entire string. Indeed, studies on viral DNA packaging might lead to the development of new antiviral drugs. Recent elucidation of the mechanism of the viral double-stranded DNA (dsDNA)-packaging motor with sequential one-way revolving motion will promote the development of potent antiviral drugs with high specificity and efficiency. Traditionally, biomotors have been classified into two categories: linear and rotation motors. Recently discovered was a third type of biomotor, including the viral DNA-packaging motor, beside the bacterial DNA translocases, that uses a revolving mechanism without rotation. By analogy, rotation resembles the Earth's rotation on its own axis, while revolving resembles the Earth's revolving around the Sun (see animations at http://rnanano.osu.edu/movie.html). Herein, we review the structures of viral dsDNA-packaging motors, the stoichiometries of motor components, and the motion mechanisms of the motors. All viral dsDNA-packaging motors, including those of dsDNA/dsRNA bacteriophages, adenoviruses, poxviruses, herpesviruses, mimiviruses, megaviruses, pandoraviruses, and pithoviruses, contain a high-stoichiometry machine composed of multiple components that work cooperatively and sequentially. Thus, it is an ideal target for potent drug development based on the power function of the stoichiometries of target complexes that work sequentially. Viruses reproduce themselves in host cells. Their intracellular parasitic nature poses a great challenge to antiviral drug development. Nevertheless, significant progress in antiviral drug discovery, such as new treatments for HIV (1), hepatitis B virus (2), herpesvirus (3), and influenza virus (4), has been made. Even though different approaches to new drug development, such as improving drug target binding affinity (5) and finding new targets with novel pharmacological mechanisms (6), have been explored, new infectious pandemic viruses that greatly threaten human health still emerge sporadically. In addition, the emergence of drug resistance necessitates new drug development. Highly potent drugs with elevated specificity are needed for overcoming viral diseases.In viral reproduction, the key step of genome packaging is usually accomplished by a biomotor using ATP. Linear doublestranded DNA (dsDNA) or dsRNA viruses package their genomes into preformed procapsids. This group includes dsDNA/dsRNA bacteriophages (7), adenoviruses (8), poxviruses (9, 120), herpesviruses (10, 11), mimiviruses, megavir...

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Torque Generation Mechanism of F1-ATPase upon NTP Binding

Cited by 15 publications

References 45 publications

Dissecting the role of the γ-subunit in the rotary–chemical coupling and torque generation of F ₁ -ATPase

Dissecting the role of the γ-subunit in the rotary–chemical coupling and torque generation of F ₁ -ATPase

Catalytic robustness and torque generation of the F1-ATPase

Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism

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Torque Generation Mechanism of F1-ATPase upon NTP Binding

Cited by 15 publications

References 45 publications

Dissecting the role of the γ-subunit in the rotary–chemical coupling and torque generation of F 1 -ATPase

Dissecting the role of the γ-subunit in the rotary–chemical coupling and torque generation of F 1 -ATPase

Catalytic robustness and torque generation of the F1-ATPase

Development of Potent Antiviral Drugs Inspired by Viral Hexameric DNA-Packaging Motors with Revolving Mechanism

Contact Info

Product

Resources

About

Dissecting the role of the γ-subunit in the rotary–chemical coupling and torque generation of F ₁ -ATPase

Dissecting the role of the γ-subunit in the rotary–chemical coupling and torque generation of F ₁ -ATPase