6TXR

Structural insights into cubane-modified aptamer recognition of a malaria biomarker

Summary for 6TXR

• Entry DOI: 10.2210/pdb6txr/pdb
• Descriptor: L-lactate dehydrogenase, ~{N}-[2-(1,2,3-triazol-1-yl)ethyl]cubane-1-carboxamide, 2'-DEOXYGUANOSINE-5'-MONOPHOSPHATE, ... (7 entities in total)
• Functional Keywords: aptamer, cubamer, pvldh, dna
• Biological source: Plasmodium vivax (malaria parasite P. vivax)
• Total number of polymer chains: 4
• Total formula weight: 161146.16

Authors

Cheung, Y.,Roethlisberger, P.,Mechaly, A.,Weber, P.,Wong, A.,Lo, Y.,Haouz, A.,Savage, P.,Hollenstein, M.,Tanner, J. (deposition date: 2020-01-14, release date: 2020-07-15, Last modification date: 2024-01-24)

Primary citation

Cheung, Y.W.,Rothlisberger, P.,Mechaly, A.E.,Weber, P.,Levi-Acobas, F.,Lo, Y.,Wong, A.W.C.,Kinghorn, A.B.,Haouz, A.,Savage, G.P.,Hollenstein, M.,Tanner, J.A.
Evolution of abiotic cubane chemistries in a nucleic acid aptamer allows selective recognition of a malaria biomarker.
Proc.Natl.Acad.Sci.USA, 117:16790-16798, 2020

PubMed Abstract: Nucleic acid aptamers selected through systematic evolution of ligands by exponential enrichment (SELEX) fold into exquisite globular structures in complex with protein targets with diverse translational applications. Varying the chemistry of nucleotides allows evolution of nonnatural nucleic acids, but the extent to which exotic chemistries can be integrated into a SELEX selection to evolve nonnatural macromolecular binding interfaces is unclear. Here, we report the identification of a cubane-modified aptamer (cubamer) against the malaria biomarker lactate dehydrogenase (PvLDH). The crystal structure of the complex reveals an unprecedented binding mechanism involving a multicubane cluster within a hydrophobic pocket. The binding interaction is further stabilized through hydrogen bonding via cubyl hydrogens, previously unobserved in macromolecular binding interfaces. This binding mechanism allows discriminatory recognition of over lactate dehydrogenase, thereby distinguishing these highly conserved malaria biomarkers for diagnostic applications. Together, our data demonstrate that SELEX can be used to evolve exotic nucleic acids bearing chemical functional groups which enable remarkable binding mechanisms which have never been observed in biology. Extending to other exotic chemistries will open a myriad of possibilities for functional nucleic acids.

PubMed: 32631977
DOI: 10.1073/pnas.2003267117

Experimental method

X-RAY DIFFRACTION (2.5 Å)