Journal
STRUCTURE
Volume 26, Issue 1, Pages 40-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2017.11.008
Keywords
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Funding
- Agence Nationale de la Recherche [ANR-15-CE11-0003-01]
- Agence Nationale de Recherche sur le Sida et les hepatites virales (ANRS) [ECTZ18552]
- FRISBI [ANR-10-INSB-05-02]
- GRAL [ANR-10-LABX-49-01]
- EI3POD postdoctoral program (EMBL/EU Marie Curie Actions Cofund)
- Italian Association for Cancer Research (AIRC) [IG 18883]
- Agence Nationale de la Recherche (ANR) [ANR-15-CE11-0003] Funding Source: Agence Nationale de la Recherche (ANR)
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Synthesis and scission of phosphodiester bonds in DNA and RNA regulate vital processes within the cell. Enzymes that catalyze these reactions operate mostly via the recognized two-metal-ion mechanism. Our analysis reveals that basic amino acids and monovalent cations occupy structurally conserved positions nearby the active site of many two-metal-ion enzymes for which high-resolution (< 3 angstrom) structures are known, including DNA and RNA polymerases, nucleases such as Cas9, and splicing ribozymes. Integrating multiple-sequence and structural alignments with molecular dynamics simulations, electrostatic potential maps, and mutational data, we found that these elements always interact with the substrates, suggesting that they may play an active role for catalysis, in addition to their electrostatic contribution. We discuss possible mechanistic implications of this expanded twometal- ion architecture, including inferences on medium-resolution cryoelectron microscopy structures. Ultimately, our analysis may inspire future experiments and strategies for enzyme engineering or drug design to modulate nucleic acid processing.
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