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PreprintCited by 10Protein Structure and DynamicsAdvanced Electron Microscopy Techniques and ApplicationsEnzyme Structure and Function

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Conformational Landscapes of a Class I Ribonucleotide Reductase Complex during Turnover Reveal Intrinsic Dynamics and Asymmetry

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Xu, Da, Thomas, William C., Burnim, Audrey A., Ando, Nozomi·2024·Nature Communications
DOI 10.1101/2024.06.16.599213PMC PMC11903788

Preprint — published as 10.1038/s41467-025-57735-4

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Abstract

Understanding the structural dynamics associated with enzymatic catalysis has been a long-standing goal of biochemistry. With the advent of modern cryo-electron microscopy (cryo-EM), it has become conceivable to redefine a protein’s structure as the continuum of all conformations and their distributions. However, capturing and interpreting this information remains challenging. Here, we use classification and deep-learning-based analyses to characterize the conformational heterogeneity of a class I ribonucleotide reductase (RNR) during turnover. By converting the resulting information into physically interpretable 2D conformational landscapes, we demonstrate that RNR continuously samples a wide range of motions while maintaining surprising asymmetry to regulate the two halves of its turnover cycle. Remarkably, we directly observe the appearance of highly transient conformations needed for catalysis, as well as the interaction of RNR with its endogenous reductant thioredoxin also contributing to the asymmetry and dynamics of the enzyme complex. Overall, this work highlights the role of conformational dynamics in regulating key steps in enzyme mechanisms.

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Metadata

Authors
Xu, D., Thomas, W. C., Burnim, A. A., & Ando, N.
Affiliations
  • Cornell University (US)
  • Princeton University (US)
Corresponding author
Ando, Nozomi
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2024-06-17
Volume
16
Issue
1
Pages
2458-2458
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2024.06.16.599213
PMC
PMC11903788
OpenAlex
W4408367378
Cited by
10
References
1
Citations by year
2026: 6 · 2025: 3 · 2024: 1
FWCI
2.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Science Foundation (1942668)
  • U.S. Department of Health and Human Services (U24 GM129539)
  • Simons Foundation (SF 349247)
  • National Institutes of Health
  • National Institute of General Medical Sciences (U24GM129539)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
class I ribonucleotide reductase, conformational dynamics, conformational landscape, enzyme turnover, thioredoxin, enzyme mechanism, protein complex dynamics, deep learning classification
MeSH terms
Models, Molecular, Protein Conformation, Ribonucleotide Reductases, Thioredoxins, Cryoelectron Microscopy

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