Non-helical DNA Triplex Forms a Unique Aptamer Scaffold for High Affinity Recognition of Nerve Growth Factor

Discerning the structural building blocks of macromolecules is essential for understanding their folding and function. For a new generation of modified nucleic acid ligands (called slow off-rate modified aptamers or SOMAmers), we previously observed essential functions of hydrophobic aromatic side c...

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Bibliographic Details
Published in:Structure (London) 2015-07, Vol.23 (7), p.1293-1304
Main Authors: Jarvis, Thale C., Davies, Douglas R., Hisaminato, Akihiko, Resnicow, Daniel I., Gupta, Shashi, Waugh, Sheela M., Nagabukuro, Akira, Wadatsu, Takashi, Hishigaki, Haretsugu, Gawande, Bharat, Zhang, Chi, Wolk, Steven K., Mayfield, Wesley S., Nakaishi, Yuichiro, Burgin, Alex B., Stewart, Lance J., Edwards, Thomas E., Gelinas, Amy D., Schneider, Daniel J., Janjic, Nebojsa
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Base Sequence
Binding Sites
Crystallography, X-Ray
DNA - chemistry
Humans
Hydrophobic and Hydrophilic Interactions
Molecular Sequence Data
Nerve Growth Factor - chemistry
Nerve Growth Factor - physiology
Protein Binding
Protein Structure, Secondary
SELEX Aptamer Technique
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Summary:Discerning the structural building blocks of macromolecules is essential for understanding their folding and function. For a new generation of modified nucleic acid ligands (called slow off-rate modified aptamers or SOMAmers), we previously observed essential functions of hydrophobic aromatic side chains in the context of well-known nucleic acid motifs. Here we report a 2.45-Å resolution crystal structure of a SOMAmer complexed with nerve growth factor that lacks any known nucleic acid motifs, instead adopting a configuration akin to a triangular prism. The SOMAmer utilizes extensive hydrophobic stacking interactions, non-canonical base pairing and irregular purine glycosidic bond angles to adopt a completely non-helical, compact S-shaped structure. Aromatic side chains contribute to folding by creating an unprecedented intercalating zipper-like motif and a prominent hydrophobic core. The structure provides compelling rationale for potent inhibitory activity of the SOMAmer and adds entirely novel motifs to the repertoire of structural elements uniquely available to SOMAmers. [Display omitted] •A high affinity modified DNA aptamer binds and neutralizes nerve growth factor•The co-crystal structure reveals an unprecedented triangular prism DNA structure•DNA structure is completely non-helical with unusual base pairings and bond angles•Primarily hydrophobic contacts with few H bonds at complex interface Jarvis et al. report the structure of a modified DNA aptamer bound to beta nerve growth factor. The aptamer folds into an unusual configuration that lacks any known nucleic acid structural motifs, while hydrophobic modifications at the 5-position of deoxyuridine provide enhanced chemical diversity for unique intra- and intermolecular interactions.
ISSN:0969-2126
1878-4186
DOI:10.1016/j.str.2015.03.027