Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 141, Issue 27, Pages 10770-10776Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b03663
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Funding
- European Molecular Biology Organization (EMBO) [ALTF 103-2018]
- Agence Nationale de la Recherche [ANR-15-CE11-0003-01]
- Agence Nationale de Recherche sur le Sida et les hepatites virales (ANRS) [ECTZ18552]
- ITMO Cancer [18CN047-00]
- FRISBI [ANR-10-INSB-05-02]
- GRAL within the Grenoble Partnership for Structural Biology (PSB) [ANR-10-LABX-49-01]
- 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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Metal-dependent DNA and RNA nucleases are enzymes that cleave nucleic acids with great efficiency and precision. These enzyme-mediated hydrolytic reactions are fundamental for the replication, repair, and storage of genetic information within the cell. Here, extensive classical and quantum-based free-energy molecular simulations show that a cation-pi interaction is transiently formed in situ at the metal core of Bacteriophage-lambda Exonuclease (Exo-lambda), during catalysis. This noncovalent interaction (Lys131-Tyr154) triggers nucleophile activation for nucleotide excision. Then, our simulations also show the oscillatory dynamics and swinging of the newly formed cation-pi dyad, whose conformational change may favor proton release from the cationic Lys131 to the bulk solution, thus restoring the precatalytic protonation state in Exo-lambda. Altogether, we report on the novel mechanistic character of cation-pi interactions for catalysis. Structural and bioinformatic analyses support that flexible orientation and transient formation of mobile cation-pi interactions may represent a common catalytic strategy to promote nucleic acid hydrolysis in DNA and RNA nucleases.
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