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4zbn

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

Structural highlights

4zbn is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.447Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NGF_HUMAN Defects in NGF are the cause of hereditary sensory and autonomic neuropathy type 5 (HSAN5) [MIM:608654. The hereditary sensory and autonomic neuropathies are a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN5 patients manifest loss of pain perception and impaired temperature sensitivity, ulcers, and in some cases self-mutilation. The autonomic involvement is variable.^[1] ^[2] ^[3]

Function

NGF_HUMAN Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems. Extracellular ligand for the NTRK1 and NGFR receptors, activates cellular signaling cascades through those receptor tyrosine kinase to regulate neuronal proliferation, differentiation and survival.

Publication Abstract from PubMed

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-A 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.

Non-helical DNA Triplex Forms a Unique Aptamer Scaffold for High Affinity Recognition of Nerve Growth Factor.,Jarvis TC, Davies DR, Hisaminato A, Resnicow DI, Gupta S, Waugh SM, Nagabukuro A, Wadatsu T, Hishigaki H, Gawande B, Zhang C, Wolk SK, Mayfield WS, Nakaishi Y, Burgin AB, Stewart LJ, Edwards TE, Gelinas AD, Schneider DJ, Janjic N Structure. 2015 May 13. pii: S0969-2126(15)00145-8. doi:, 10.1016/j.str.2015.03.027. PMID:26027732^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G, Holmgren G, Holmberg D, Holmberg M. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet. 2004 Apr 15;13(8):799-805. Epub 2004 Feb 19. PMID:14976160 doi:10.1093/hmg/ddh096
↑ Carvalho OP, Thornton GK, Hertecant J, Houlden H, Nicholas AK, Cox JJ, Rielly M, Al-Gazali L, Woods CG. A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy. J Med Genet. 2011 Feb;48(2):131-5. doi: 10.1136/jmg.2010.081455. Epub 2010 Oct, 26. PMID:20978020 doi:10.1136/jmg.2010.081455
↑ Davidson G, Murphy S, Polke J, Laura M, Salih M, Muntoni F, Blake J, Brandner S, Davies N, Horvath R, Price S, Donaghy M, Roberts M, Foulds N, Ramdharry G, Soler D, Lunn M, Manji H, Davis M, Houlden H, Reilly M. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. J Neurol. 2012 Aug;259(8):1673-85. PMID:22302274 doi:10.1007/s00415-011-6397-y
↑ Jarvis TC, Davies DR, Hisaminato A, Resnicow DI, Gupta S, Waugh SM, Nagabukuro A, Wadatsu T, Hishigaki H, Gawande B, Zhang C, Wolk SK, Mayfield WS, Nakaishi Y, Burgin AB, Stewart LJ, Edwards TE, Gelinas AD, Schneider DJ, Janjic N. Non-helical DNA Triplex Forms a Unique Aptamer Scaffold for High Affinity Recognition of Nerve Growth Factor. Structure. 2015 May 13. pii: S0969-2126(15)00145-8. doi:, 10.1016/j.str.2015.03.027. PMID:26027732 doi:http://dx.doi.org/10.1016/j.str.2015.03.027