9DN4

Crystal structure of a SARS-CoV-2 20-mer RNA in complex with FAB BL3-6S97N

Summary for 9DN4

• Entry DOI: 10.2210/pdb9dn4/pdb
• Descriptor: FAB BL3-6S97N HEAVY CHAIN, FAB BL3-6S97N LIGHT CHAIN, RNA (5'-R(P*CP*UP*CP*GP*UP*CP*UP*GP*AP*AP*AP*CP*AP*CP*GP*GP*AP*GP*AP*G)-3'), ... (7 entities in total)
• Functional Keywords: fab, fab bl3-6s97, fab:rna complex, immune system-rna complex, immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 6
• Total formula weight: 118263.21

Authors

Lovell, S.,Cooper, A.,Battaile, K.P.,Hegde, S.,Wang, J. (deposition date: 2024-09-16, release date: 2024-09-25, Last modification date: 2025-07-02)

Primary citation

Hegde, S.,Akhter, S.,Tang, Z.,Qi, C.,Yu, C.,Lewicka, A.,Liu, Y.,Koirala, K.,Reibarkh, M.,Battaile, K.P.,Cooper, A.,Lovell, S.,Holmstrom, E.D.,Wang, X.,Piccirilli, J.A.,Gao, Q.,Miao, Y.,Wang, J.
Mechanistic studies of small molecule ligands selective to RNA single G bulges.
Nucleic Acids Res., 53:-, 2025

PubMed Abstract: Small-molecule RNA binders have emerged as an important pharmacological modality. A profound understanding of the ligand selectivity, binding mode, and influential factors governing ligand engagement with RNA targets is the foundation for rational ligand design. Here, we report a novel class of coumarin derivatives exhibiting selective binding affinity towards single G RNA bulges. Harnessing the computational power of all-atom Gaussian accelerated molecular dynamics simulations, we unveiled a rare minor groove binding mode of the ligand with a key interaction between the coumarin moiety and the G bulge. This predicted binding mode is consistent with results obtained from structure-activity relationship studies and transverse relaxation measurements by nuclear magnetic resonance spectroscopy. We further generated 444 molecular descriptors from 69 coumarin derivatives and identified key contributors to the binding events, such as charge state and planarity, by lasso (least absolute shrinkage and selection operator) regression. Our work deepened the understanding of RNA-small molecule interactions and integrated a new framework for the rational design of selective small-molecule RNA binders.

PubMed: 40557870
DOI: 10.1093/nar/gkaf559

Experimental method

X-RAY DIFFRACTION (1.9 Å)