title: Non-helical DNA Triplex Forms a Unique Aptamer Scaffold for High Affinity Recognition of Nerve Growth Factor.
abstract: 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.
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Thale C
authors.initials: TC
authors.lastname: Jarvis
authors.affiliation: Beryllium, 7869 Northeast Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Davies
authors.affiliation: Otsuka Pharmaceutical Co., Ltd., Institute of Biomedical Innovation, 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Hisaminato
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Resnicow
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Shashi
authors.initials: S
authors.lastname: Gupta
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Sheela M
authors.initials: SM
authors.lastname: Waugh
authors.affiliation: Otsuka Pharmaceutical Co., Ltd., Institute of Biomedical Innovation, 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nagabukuro
authors.affiliation: Otsuka Pharmaceutical Co., Ltd., Institute of Biomedical Innovation, 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Wadatsu
authors.affiliation: Otsuka Pharmaceutical Co., Ltd., Institute of Biomedical Innovation, 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: Haretsugu
authors.initials: H
authors.lastname: Hishigaki
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Gawande
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Wolk
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Wesley S
authors.initials: WS
authors.lastname: Mayfield
authors.affiliation: Otsuka Pharmaceutical Co., Ltd., Medicinal Chemistry Research Institute, 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nakaishi
authors.affiliation: The Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Burgin
authors.affiliation: The Institute for Protein Design, University of Washington, 3946 West Stevens Way Northeast, Seattle, WA 98195-1655, USA.
authors.forename: Lance J
authors.initials: LJ
authors.lastname: Stewart
authors.affiliation: Beryllium, 7869 Northeast Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Edwards
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Gelinas
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schneider
authors.affiliation: SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA. Electronic address: njanjic@somalogic.com.
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Janjic
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000737:chemistry* / Q000502:physiology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D052156:SELEX Aptamer Technique
chemical_list: C051802:triplex DNA; D004247:DNA; D020932:Nerve Growth Factor