Structure of a ribonucleotide reductase R2 protein radical

Lebrette, Hugo; Srinivas, Vivek; John, Juliane; Aurelius, Oskar; Kumar, Rohit; Lundin, Daniel; Brewster, Aaron S.; Bhowmick, Asmit; Sirohiwal, Abhishek; Kim, In-Sik; Gul, Sheraz; Pham, Cindy; Sutherlin, Kyle D.; Simon, Philipp; Butryn, Agata; Aller, Pierre; Orville, Allen M.; Fuller, Franklin D.; Alonso-Mori, Roberto; Batyuk, Alexander; Sauter, Nicholas K.; Yachandra, Vittal K.; Yano, Junko; Kaila, Ville R. I.; Sjöberg, Britt-Marie; Kern, Jan; Roos, Katarina; Högbom, Martin

doi:10.1126/science.adh8160

Cited by 11 publications

(9 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, N3UDP traps a longlived radical in the α2 active site 117 that coincides with the disappearance of Y122•, 118 and produces a stalled αα'ββ' supercomplex. Again, the state that forms upon radical translocation is distinct from that of met-β2, 113 and though comparisons between resting state β2 and met-β2 reveal significant changes in the position of Y122, 115,119,120 as well as changes to the H-bond network within β, 121 these changes may not be relevant to those taking place upon radical translocation. 122 By incorporating FnY residues with varied redox potentials and pKas, the thermodynamic reaction landscape of the PCET pathway has been mapped (Figure 4.2c).…”

Section: Protein Conformational Changes Trigger Pcet At β-Y122mentioning

confidence: 94%

“…[112][113][114] Here, it is important to emphasize a subtle yet critical difference between these active structures, 101 and related inactive structures. 115 When PCET is initiated, β-Y122• is reduced by 1eand 1H + (Figure 4.2(a), blue). The resultant state differs from that produced through exogenous reduction of β-Y122• by 1eand 1H + , which yields an inactive form of β2, termed met-β2 (Figure 4.2(a), red), that is incapable of initiating catalysis or binding tightly to α2.…”

Section: The Rnr Pcet Pathway Transiently Oxidizes Amino Acids β-Y122...mentioning

confidence: 99%

“…120,126 In-line with this suggestion, XFEL serial femtosecond crystallography was recently employed to solve the crystal structure of the radical resting state of β2 from a class 1e RNR. 115 In class 1e RNRs, the Fe III 2(μ-O)/Y • cofactor is replaced by a 3,4-dihydroxyphenylalanine radical (DOPA • ). 127,128 The work revealed that the resting state exhibits a 2.41 ± 0.04 Å H-bond interaction between the meta-O(H) of DOPA• (the radical is thought to reside on the para-O) and D88, which sits in an analogous position to D84 of the E. coli class Ia enzyme.…”

Section: Protein Conformational Changes Trigger Pcet At β-Y122mentioning

confidence: 99%

“…The authors also note that a comparison of the active and resting structures reveals restructuring of the protein surface interacting with α2 upon docking and initiation of radical translocation. 115…”

Section: Protein Conformational Changes Trigger Pcet At β-Y122mentioning

confidence: 99%

See 3 more Smart Citations

Conformational Control over Proton-Coupled Electron Transfer in Metalloenzymes

Fatima,

Olshansky

2024

Preprint

View full text Add to dashboard Cite

From the reduction of dinitrogen to the oxidation of water, the chemical transformations catalyzed by metalloenzymes underlie global geo- and biochemical cycles. These reactions represent some of the most kinetically and thermodynamically challenging processes known. They require the complex choreography of nature’s fundamental building blocks: electrons and protons, to be carried out with utmost precision and accuracy; mistimed synchronicity can be fatal. Gated by macrostructural conformational changes, the rate-determining steps of catalysis in many of these enzymes consist of protein structural rearrangements. Accordingly, a pattern emerges in which it appears that nature has evolved to leverage changes in macromolecular protein structure to control changes in the metallocofactor microstructure. This critical review defines (where possible) and discusses the detailed molecular mechanisms of how metalloenzymes are able to efficiently convert allosteric binding energy into activation energy through conformational gating. Here, the proton-coupled electron transfer (PCET) mechanisms in biology stand as a paradigm for the interplay between molecular and electronic structural control. Taking nitrogenase, photosystem II, and ribonucleotide reductase as examples, we present the culmination of decades of study on each of these systems to clarify what is known regarding the interplay between structural changes and functional outcomes in these metalloenzyme linchpins.

show abstract

Section: Protein Conformational Changes Trigger Pcet At β-Y122mentioning

confidence: 94%

Section: The Rnr Pcet Pathway Transiently Oxidizes Amino Acids β-Y122...mentioning

confidence: 99%

Section: Protein Conformational Changes Trigger Pcet At β-Y122mentioning

confidence: 99%

Section: Protein Conformational Changes Trigger Pcet At β-Y122mentioning

confidence: 99%

See 2 more Smart Citations

Conformational Control over Proton-Coupled Electron Transfer in Metalloenzymes

Fatima,

Olshansky

2024

Preprint

View full text Add to dashboard Cite

show abstract

“…The molecular mechanism of action of HU is well known today [ 18 , 19 , 20 , 21 , 22 ]. Hydroxyurea acts as an inhibitor of DNA replication by affecting the activity of ribonucleotide reductase (RNR).…”

Section: Introductionmentioning

confidence: 99%

Hydration of N-Hydroxyurea from Ab Initio Molecular Dynamics Simulations

Balicki,

Śmiechowski

2024

Molecules

View full text Add to dashboard Cite

N-Hydroxyurea (HU) is an important chemotherapeutic agent used as a first-line treatment in conditions such as sickle cell disease and β-thalassemia, among others. To date, its properties as a hydrated molecule in the blood plasma or cytoplasm are dramatically understudied, although they may be crucial to the binding of HU to the radical catalytic site of ribonucleotide reductase, its molecular target. The purpose of this work is the comprehensive exploration of HU hydration. The topic is studied using ab initio molecular dynamic (AIMD) simulations that apply a first principles representation of the electron density of the system. This allows for the calculation of infrared spectra, which may be decomposed spatially to better capture the spectral signatures of solute–solvent interactions. The studied molecule is found to be strongly hydrated and tightly bound to the first shell water molecules. The analysis of the distance-dependent spectra of HU shows that the E and Z conformers spectrally affect, on average, 3.4 and 2.5 of the closest H2O molecules, respectively, in spheres of radii of 3.7 Å and 3.5 Å, respectively. The distance-dependent spectra corresponding to these cutoff radii show increased absorbance in the red-shifted part of the water OH stretching vibration band, indicating local enhancement of the solvent’s hydrogen bond network. The radially resolved IR spectra also demonstrate that HU effortlessly incorporates into the hydrogen bond network of water and has an enhancing effect on this network. Metadynamics simulations based on AIMD methodology provide a picture of the conformational equilibria of HU in solution. Contrary to previous investigations of an isolated HU molecule in the gas phase, the Z conformer of HU is found here to be more stable by 17.4 kJ·mol−1 than the E conformer, pointing at the crucial role that hydration plays in determining the conformational stability of solutes. The potential energy surface for the OH group rotation in HU indicates that there is no intramolecular hydrogen bond in Z-HU in water, in stark contrast to the isolated solute in the gas phase. Instead, the preferred orientation of the hydroxyl group is perpendicular to the molecular plane of the solute. In view of the known chaotropic effect of urea and its N-alkyl-substituted derivatives, N-hydroxyurea emerges as a unique urea derivative that exhibits a kosmotropic ordering of nearby water. This property may be of crucial importance for its binding to the catalytic site of ribonucleotide reductase with a concomitant displacement of a water molecule.

show abstract

Synthesis of Non‐canonical Tryptophan Variants via Rh‐catalyzed C−H Functionalization of Anilines

Huang,

Ying,

Seyedsayamdost

2024

Angewandte Chemie

View full text Add to dashboard Cite

Tryptophan and its non‐canonical variants play critical roles in pharmaceutical molecules and enzymes. Facile access to this privileged class of amino acids from readily available building blocks remains a long‐standing challenge. Here, we report a regioselective synthesis of non‐canonical tryptophans bearing C4‐C7 substituents via Rh‐catalyzed annulation between structurally diverse tert‐butyloxycarbonyl (Boc)‐protected anilines and alkynyl chlorides readily prepared from amino acid building blocks. This transformation harnesses Boc‐directed C–H metalation and demetalation to afford a wide range of C2‐unsubstituted indole products in a redox‐neutral fashion. This umpolung approach compared to the classic Larock indole synthesis offers a novel mechanism for heteroarene annulation and will be useful for the synthesis of natural products and drug molecules containing non‐canonical tryptophan residues in a highly regioselective manner.

show abstract

Structure of a ribonucleotide reductase R2 protein radical

Cited by 11 publications

References 69 publications

Conformational Control over Proton-Coupled Electron Transfer in Metalloenzymes

Conformational Control over Proton-Coupled Electron Transfer in Metalloenzymes

Hydration of N-Hydroxyurea from Ab Initio Molecular Dynamics Simulations

Synthesis of Non‐canonical Tryptophan Variants via Rh‐catalyzed C−H Functionalization of Anilines

Contact Info

Product

Resources

About