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Volume 10, Issue 8 (Suppl)
J Proteomics Bioinform, an open access journal
ISSN: 0974-276X
Structural Biology 2017
September 18-20, 2017
9
th
International Conference on
Structural Biology
September 18-20, 2017 Zurich, Switzerland
Structural insights from aptamers with base modifications
Nebojsa Janjic
SomaLogic, Inc., USA
Statement of the Problem:
The ability to fold into distinct three-dimensional structures is the basis of high affinity and
specificity characteristic of aptamer binding to their targets. We have recently introduced base modifications that increase
chemical diversity of functional groups front-loaded in randomized nucleic acid libraries from which aptamers are selected.
Such modifications have allowed us to identify high-affinity aptamers to many protein targets previously considered “difficult”
with conventional nucleic acid libraries. At the same time, our ability to predict the structures of modified aptamers with
conventional nucleic acid folding rules was severely compromised, suggesting new rules for folding.
Methodology & Theoretical Orientation:
We examined, published structures of sixteen aptamers co-crystallized with their
protein targets, including three aptamers with base modifications we reported recently.
Findings:
In contrast to small molecules, which are entirely encaged by aptamers, proteins present large surfaces with distinct
features that are recognized by complementary surfaces on aptamers. The size of these interaction surfaces is comparable to
those observed with antibodies, although for aptamers, the size range is wider on both small and large extremes. The highly
flexible phosphodiester backbone allows assembly of known as well as novel nucleic acid motifs into precise three-dimensional
structures that orient often discontiguous aptamer regions toward their protein targets in a manner that creates surfaces with
exquisite shape complementarity. Base modifications with hydrophobic side chains allow occupancy of distinctly hydrophobic
pockets on proteins and create novel structural elements that illustrate the profound role modified nucleotides play in both
folding and binding.
Conclusion & Significance:
These observations provide compelling structural rationale for the observed high affinity and
specificity with which aptamers recognize their protein targets, and show us that the lexicon of structural features accessible to
nucleic acid ligands can be vastly expanded with chemical modifications of nucleic acid libraries.
Biography
Nebojsa Janjic has been Chief Science Officer at SomaLogic, Inc. since January 2009. Prior to joining SomaLogic, he was a Founder and CSO at Replidyne, Inc.,
a Biotechnology company focusing on the development of new small-molecule antibacterial agents. Prior to Replidyne, he was Senior Director of drug discovery
at NeXstar Pharmaceuticals, where his contributions include the discovery and early development of Macugen, the first aptamer to receive FDA approval and
the first VEGF inhibitor developed for the treatment for macular degeneration. As CSO at SomaLogic, he is involved in developing a new generation of modified
aptamers and identifying opportunities for their use in science and medicine. He has received his Bachelor's degree in Molecular Biology and PhD in Physical
Organic Chemistry from the University of Washington in Seattle and completed his Postdoctoral training at the Scripps Research Institute in La Jolla as a Cancer
Research Institute Fellow.
njanjic@somalogic.comNebojsa Janjic, J Proteomics Bioinform 2017, 10:8(Suppl)
DOI: 10.4172/0974-276X-C1-0100
Figure1:
Crystal structures of PDGF-BB (left), IL-6 (middle) and NGF (right) bound
to their respective modified aptamers. Modified nucleotides are shown in red.