Convergent allostery in ribonucleotide reductase

Thomas, William G.; Brooks, F. Phil; Burnim, Audrey A.; Bacik, J.P.; Stubbe, JoAnne; Kaelber, Jason T.; Chen, J.Z.; Ando, Nozomi

doi:10.1038/s41467-019-10568-4

Cited by 31 publications

(71 citation statements)

References 78 publications

(148 reference statements)

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“…Importantly, the rate of pressure decline (−dP/dt) is also significantly increased. Data from cardiac and skeletal muscle at multiple structural scales suggest that faster contraction results from increased cross-bridge binding and cycling kinetics (Regnier & Homsher, 1998;Regnier et al 1998a;Thomas et al 2019). However, the mechanism by which dATP affects relaxation is less clear.…”

Section: Introductionmentioning

confidence: 99%

Myosin dynamics during relaxation in mouse soleus muscle and modulation by 2′‐deoxy‐ATP

Childers

Murray

et al. 2020

The Journal of Physiology

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Skeletal muscle relaxation has been primarily studied by assessing the kinetics of force decay. Little is known about the resultant dynamics of structural changes in myosin heads during relaxation. r The naturally occurring nucleotide 2-deoxy-ATP (dATP) is a myosin activator that enhances cross-bridge binding and kinetics. r X-ray diffraction data indicate that with elevated dATP, myosin heads were extended closer to actin in relaxed muscle and myosin heads return to an ordered, resting state after contraction more quickly. r Molecular dynamics simulations of post-powerstroke myosin suggest that dATP induces structural changes in myosin heads that increase the surface area of the actin-binding regions promoting myosin interaction with actin, which could explain the observed delays in the onset of relaxation. r This study of the dATP-induced changes in myosin may be instructive for determining the structural changes desired for other potential myosin-targeted molecular compounds to treat muscle diseases.

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Section: Introductionmentioning

confidence: 99%

Myosin dynamics during relaxation in mouse soleus muscle and modulation by 2′‐deoxy‐ATP

Childers

Murray

et al. 2020

The Journal of Physiology

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“…First, assume that the ratio of α:β is 1:1 and that α 2 β 2 is the active form. We believe this is a reasonable assumption based on the recent structures of an active E. coli Ia RNR 15 and structures of B. subtilis 43 and S. typhimurium 46 Ib RNRs.…”

Section: K D For Subunit Interactionsmentioning

confidence: 82%

“…While α alone has been found as noted above in many states, it also forms inactive complexes with β (α 4 β 4 ) in E. coli 19 and in a helical α/β fibril in B. subtilis. 43 Some have proposed that α 6 /β 2 forms exist in S. cerevisiae and human RNRs, 44 but in our opinion, the activity of this state is in question. Not much is known about the equilibria of these species and how other factors in cells affect them.…”

Section: α/β Complex Characterizationmentioning

confidence: 88%

Subunit Interaction Dynamics of Class Ia Ribonucleotide Reductases: In Search of a Robust Assay

Ravichandran,

Olshansky,

Nocera

et al. 2020

Biochemistry

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Ribonucleotide reductases (RNRs) catalyze the conversion of nucleotides (NDP) to deoxynucleotides (dNDP), in part controlling the ratios and quantities of dNTPs available for DNA replication and repair. The active form of E. coli class Ia RNR is an asymmetric α 2 β 2 complex in which α 2 contains the active site and β 2 contains the stable diferric-tyrosyl radical cofactor responsible for initiating the reduction chemistry. Each dNDP is accompanied by disulfide bond formation. We now report that β 2 can act catalytically when assaying RNR in either the absence or presence of an external reductant. In the absence of reductant, rapid chemical quench analysis of a reaction of α 2 (10 μM), substrate, and effector with variable amounts of β 2 (0.1, 1 or 10 μM) yields 3 dCDP/α 2 at all ratios of α 2 :β 2 with a rate constant of 8-9 s −1 , associated with a rate limiting conformational change(s). Stopped-flow fluorescence spectroscopy with a fluorophore-labeled β reveals that the rate constants for subunit association (163 ± 7 μM −1 s −1) and dissociation (75 ± 10 s −1) are fast relative to turnover, consistent with catalytic β 2. When assaying in the presence of an external reducing system, the turnover number is dictated by the ratio of α 2 :β 2 , their concentrations, and the concentration and nature of the reducing system; the

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“…Altered molecular weights using SEC analysis can be attributed to unusual, nonglobular shapes (α6β2) or altered quaternary structure(s). For example, fibril structures have been reported with human α and ATP (27) as well as with Bacillus subtilis class Ib (α/β) RNRs (75).…”

Section: F 2 Cdpmentioning

confidence: 99%

Ribonucleotide Reductases: Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets

Greene

Kang

Cui

et al. 2020

Annu. Rev. Biochem.

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144

195

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Ribonucleotide reductases (RNRs) catalyze the de novo conversion of nucleotides to deoxynucleotides in all organisms, controlling their relative ratios and abundance. In doing so, they play an important role in fidelity of DNA replication and repair. RNRs’ central role in nucleic acid metabolism has resulted in five therapeutics that inhibit human RNRs. In this review, we discuss the structural, dynamic, and mechanistic aspects of RNR activity and regulation, primarily for the human and Escherichia coli class Ia enzymes. The unusual radical-based organic chemistry of nucleotide reduction, the inorganic chemistry of the essential metallo-cofactor biosynthesis/maintenance, the transport of a radical over a long distance, and the dynamics of subunit interactions all present distinct entry points toward RNR inhibition that are relevant for drug discovery. We describe the current mechanistic understanding of small molecules that target different elements of RNR function, including downstream pathways that lead to cell cytotoxicity. We conclude by summarizing novel and emergent RNR targeting motifs for cancer and antibiotic therapeutics.

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Convergent allostery in ribonucleotide reductase

Cited by 31 publications

References 78 publications

Myosin dynamics during relaxation in mouse soleus muscle and modulation by 2′‐deoxy‐ATP

Myosin dynamics during relaxation in mouse soleus muscle and modulation by 2′‐deoxy‐ATP

Subunit Interaction Dynamics of Class Ia Ribonucleotide Reductases: In Search of a Robust Assay

Ribonucleotide Reductases: Structure, Chemistry, and Metabolism Suggest New Therapeutic Targets

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