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The pentose sugar in DNA is deoxyribose, while in RNA the pentose sugar is ribose. The difference between the sugars is the presence of the hydroxyl group on the ribose's second carbon and a hydrogen on the deoxyribose's second carbon. The phosphate residue attaches to the hydroxyl group of the 5′ carbon of one sugar and the hydroxyl group of the 3′ carbon of the sugar of the next nucleotide, which forms  a 5′ to 3′ phosphodiester linkage.
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Structural basis for small molecule binding to the SARS-CoV-2 nsp10-nsp14 ExoN complex.

Frank Kozielski1, Suzanne Zoë Fisher2,3,4, Shumeng Ma1

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Researchers identified new drug targets by studying the SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) nsp10-nsp14 complex. Fragment screening revealed novel binding sites, offering starting points for developing antiviral drugs.

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Area of Science:

  • Virology
  • Structural Biology
  • Drug Discovery

Background:

  • Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a global pandemic.
  • The SARS-CoV-2 non-structural proteins 10 (nsp10) and 14 (nsp14) are crucial for viral replication and are potential drug targets.
  • Nsp14's 3'-to-5' exoribonuclease (ExoN) activity, stimulated by nsp10, confers resistance to nucleoside analogue drugs by correcting errors in RNA synthesis.

Purpose of the Study:

  • To elucidate the structural basis of nsp10-nsp14 complex function and identify novel inhibition strategies.
  • To characterize conformational changes within the nsp10-nsp14 ExoN complex.
  • To discover new fragment-based starting points for developing drugs targeting the SARS-CoV-2 nsp10-nsp14 interaction.

Main Methods:

  • Crystallization of the nsp10-nsp14 ExoN complex to enable structural analysis.
  • X-ray fragment screening to identify novel binding sites on the complex.
  • Microscale thermophoresis to estimate binding affinities of identified fragments.
  • Investigation of identified sites for potential inhibition of nsp10-nsp14 protein-protein interactions.

Main Results:

  • The nsp10-nsp14 ExoN complex was crystallized, revealing distinct conformations and trapping key residues like His268 in different orientations.
  • Five novel fragment binding sites were identified at the nsp10-nsp14 interface, hinge region, and on nsp10.
  • One interface site showed a cluster of nine related fragments, enabling initial structure-activity relationship studies, and enantiomers selectively bound to different sites.

Conclusions:

  • The identified fragments represent novel starting points for structure-based drug design against SARS-CoV-2.
  • The discovered binding sites offer opportunities to develop inhibitors that disrupt the nsp10-nsp14 protein-protein interaction.
  • Understanding the conformational dynamics and fragment binding provides a foundation for developing effective antiviral therapies.